Molecular Medicine Reports Molecular Medicine Reports 1791-2997 1791-3004 D.A. Spandidos 10.3892/mmr.2021.11873 MMR-0-0-11873 Review Mechanism of herbal medicine on hypertensive nephropathy DongZhaocheng 1 2 DaiHaoran 3 FengZhandong 4 LiuWenbin 2 5 GaoYu 2 5 LiuFei 1 2 ZhangZihan 1 2 ZhangNa 2 5 DongXuan 2 5 ZhaoQihan 2 5 ZhouXiaoshan 1 DuJieli 1 LiuBaoli 2 Beijing Hospital of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing 100010, P.R. China Shunyi Branch, Beijing Traditional Chinese Medicine Hospital, Beijing 101300, P.R. China Beijing Chinese Medicine Hospital Pinggu Hospital, Beijing 101200, P.R. China Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, P.R. China Correspondence to: Dr Baoli Liu, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, 23 Meishuguanhou Street, Dongcheng, Beijing 100010, P.R. China, E-mail: liubaoli@bjzhongyi.com 04 2021 26 01 2021 23 4 234 02092020 30122020 Copyright: © Dong et al. 2021 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Hypertensive nephropathy is the most common complication of hypertension, and is one of the main causes of end-stage renal disease (ESRD) in numerous countries. The basic pathological feature of hypertensive nephropathy is arteriolosclerosis followed by renal parenchymal damage. The etiology of this disease is complex, and its pathogenesis is mainly associated with renal hemodynamic changes and vascular remodeling. Despite the increased knowledge on the pathogenesis of hypertensive nephropathy, the current clinical treatment methods are still not effective in preventing the development of the disease to ESRD. Herbal medicine, which is used to relieve symptoms, can improve hypertensive nephropathy through multiple targets. Since there are few clinical studies on the treatment of hypertensive nephropathy with herbal medicine, this article aims to review the progress on the basic research on the treatment of hypertensive nephropathy with herbal medicine, including regulation of the renin angiotensin system, inhibition of sympathetic excitation, antioxidant stress and anti-inflammatory protection of endothelial cells, and improvement of obesity-associated factors. Herbal medicine with different components plays a synergistic and multi-target role in the treatment of hypertensive nephropathy. The description of the mechanism of herbal medicine in the treatment of hypertensive nephropathy will contribute towards the progress of modern medicine.

 hypertensive nephropathy herbal medicine vascular remodeling endothelial cells renin angiotensin system National Key Research and Development Project 2019YFC1709402 National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809 81673907 81973793 Natural Science Foundation of Beijing Municipalityhttp://dx.doi.org/10.13039/501100004826 7182070 Beijing Municipal Administration of Hospitals Clinical Medicine Development XLMX201833 This study was supported by grants from the National Key Research and Development Project (grant no. 2019YFC1709402), National Natural Science Foundation of China (grant nos. 81673907 and 81973793 awarded to LB), Natural Science Foundation of Beijing Municipality (grant no. 7182070 awarded to LB) and Beijing Municipal Administration of Hospitals Clinical Medicine Development of special funding support (grant no. XLMX201833 awarded to LB). Introduction

The association between high blood pressure and the kidney is high (1,2). The kidney participates in the formation of blood pressure through the secretion of renin and the regulation of body fluids (3). The imbalance of such regulation leads to hypertension. In addition, the kidney is one of the important target organs affected by hypertension-associated damage (4,5). The renal tubules are sensitive to ischemia, and dysfunction of distal tubules concentration often occurs first, including increased nocturia, decreased urine-specific gravity and decreased urine osmotic pressure (6). Over time, proteinuria, mostly mild, may occur after glomerular ischemia, while moderate proteinuria may occur in certain patients with high blood pressure (7,8). The decrease in the glomerular filtration rate eventually leads to end-stage renal disease (ESRD). In terms of renal pathology, the kidney size is normal at the early stage, while the kidney volume is decreased at the late stage, and its surface is fine and granular. This is caused by arteriolosclerosis, which leads to renal parenchymal damage and ischemic sclerosis in certain glomeruli (9–11). Ischemic lesions are also found in the renal interstitium and tubules. In terms of treatment, the current therapeutic aim of modern medicine is only to protect the residual nephrons and to delay the progression of renal damage using antihypertensive drugs (2).

Herbal medicine has been historically used in the treatment of hypertensive nephropathy, and its clinical effect is remarkable. Therefore, it is of great clinical and economical importance to explore its mechanism of action. The present study aims to review the recent basic research on the mechanism of herbal medicine for the treatment of hypertensive nephropathy.

 Pathogenesis of hypertensive nephropathy

Hypertensive nephropathy is more common in elderly patients >50 years of age with a long history of chronic hypertension, and is more prevalent in men compared with women (12). The clinical manifestations appear later than the pathological changes (13). Hypertension usually lasts for >10 years before the gradual emergence of nocturia, mild proteinuria and other associated clinical symptoms (14). This disease is usually preceded by distal tubular dysfunction, followed by glomerular dysfunction (15,16). The patient's renal pathology starts with renal arteriopathy, followed by ischemic renal parenchymal damage (11). Renal arteriolosclerosis mainly affects the arterioles before the glomerulus, including hyaline degeneration of the glomerular arterioles, and thickening of the medium membrane of the interlobular and arcuate arteries (17,18). The reason for this is vascular endothelial damage and increased vascular cavity pressure, which results in the subcutaneous accumulation of plasma components (19,20). Hypertrophy and hyperplasia of membranous smooth muscle cells in the interlobular and arcuate arteries are accompanied by different degrees of intimal fibrosis (21). Both lesions lead to hardening and thickening of the arteriole walls, narrowing of the lumen and decreased renal blood supply, followed by ischemic renal parenchymal damage (22–24). As arteriopathy progresses, the glomerulus first undergo ischemic shrinkage, namely capillary basement membrane wrinkling, while the lumen remains open. Next, ischemic sclerosis occurs, where the basement membrane is highly wrinkled and the capillary lumen collapses (25,26). The renal tubules and interstitium are also ischemic, including tubules atrophy, thickening of the basement membrane, interstitial fibrosis and limited mononuclear cell infiltration (27,28). When parts of the glomeruli are damaged, the remaining glomeruli compensatively enhance the discharge of metabolic waste substances, eventually leading to glomerulosclerosis.

The mechanisms of hypertensive nephropathy is mainly renal hemodynamic changes and vascular remodeling caused by hypertension (29,30). When hypertension occurs, changes in renal hemodynamics will lead to changes in the function and structure of renal arterioles, which is known as vascular remodeling (31). During hypertension, the change in arteriole function is mainly manifested as increased responsiveness to vasoconstrictive substances (32,33), which results in increased vascular resistance and decreased renal plasma flow. However, in previous studies, the renal function remained normal due to increased glomerular filtration fraction. If hypertension persists, it can lead to structural changes in renal arterioles, particularly in the interlobular and arcuate arteries, and to hypertrophy and proliferation of smooth muscle cells (34,35). The mechanism is complex, and is the result of various active substances in the circulation, as well as an imbalance of vascular endothelial synthesis and secretion. For example, endothelin-1 (ET-1) is increased, while nitric oxide (NO) is decreased (36–38). Finally, the renal arteriole wall thickens, the lumen narrows, the vascular compliance decreases, the renal plasma flow further decreases and the renal function is damaged. However, not all the renal arterioles undergo hypertrophic remodeling, resulting in hypoperfusion and ischemic renal parenchymal damage. In fact, the arterioles in the other part of the kidney do not show hypertrophic remodeling, but rather compensatory hyperperfusion (39). The glomeruli, which are supplied by these arteries, also change from exhibiting hypertrophy to exhibiting focal segmental sclerosis (40). Although the purpose of hypertensive nephropathy treatment is to protect the residual nephron and delay the progression of renal damage, the key aim of the treatment is to effectively control blood pressure (4,9). Therefore, the majority of research on the treatment of hypertensive nephropathy focuses on hypertension. Moreover, relevant studies on the control and treatment of hypertensive nephropathy using traditional Chinese medicine via a variety of mechanisms also investigate hypertension (41–43). The basic studies on herbal medicine prescribed for hypertensive nephropathy are shown in Table I.

 Mechanism of herbal medicine in the treatment of hypertensive nephropathy <sec> <title>Suppression of the renin-angiotensin system (RAS)

The RAS plays an important role locally in the kidney. Angiotensin II (AngII) can directly bind to angiotensin receptors on renal arteriolar smooth muscle cells and stimulate vascular smooth muscle contraction (44). AngII also stimulates the sympathetic nerve to promote vascular smooth muscle resistance, thus leading to increased renal vascular resistance. In addition, AngII can increase sodium reabsorption through the aldosterone action on distal renal tubules, thus increasing the blood volume and leading to increased blood pressure (45). Numerous basic studies have shown that herbal medicine can play a crucial role in the treatment of hypertensive nephropathy by inhibiting RAS. Genipin, as one of the main components of Gardenia, can protect the renal function of spontaneously hypertensive rat (SHR) via the AngII-TLR/MyD88/mitogen activated protein kinase (MAPK) pathway (46). Qian Yang Yu Yin granules can suppress AngII in multiple manners. The mechanism includes alleviation of SHR and inhibition of 293T cells' effort induced by AngII through the epigenetic pathway associated with nicotinamide N-methyltransferase expression (47). The Jiangya Tongluo formula can regulate the protective effect of adrenomedullin and angiotensin in rats with hypertensive nephrosis (48). The heart-protecting musk pill can decrease the partial levels of AngII in SHR kidney, thus treating hypertensive nephropathy (49).

In addition to studies on hypertensive nephropathy, numerous studies have demonstrated that herbal medicine can show efficacy in the treatment of chronic kidney disease or hypertension by inhibiting the RAS. For example, Chrysanthemum acts as an antihypertensive by acting on the RAS (50). The water extracts of kidney bean sprouts have been demonstrated to inhibit angiotensin converting enzyme, thus exhibiting potential for lowering blood pressure (51). Alisol B 23 acetate, as one of the main ingredients of Rhizoma alismatis, can suppress the expression of constituents of the RAS, and can inhibit the epithelial-to-mesenchymal transition (EMT) in nephrectomised rats, thus lowering blood pressure, decreasing serum creatinine and preventing proteinuria (52). In addition, Alisol B 23 acetate can block the RAS/Wnt/β-catenin axis to improve podocyte injury and the EMT of HK-2 cells (53). Ergone, one of the main ingredients of Polyporus umbellatus, and pachymic acid B, one of the main ingredients of Poria cocos, have the same effect (53). In addition, poricoic acid ZA, ZF, ZG and ZH, which are important components of Poria cocos, inhibit the effect of the RAS to protect podocytes and renal tubular epithelial cells, but affect the RAS and the transforming growth factor-β1 (TGF-β1)/Smad axis (54,55). Previous studies have shown that poricoic acid ZC, ZD and ZE in Poria Cocos protect renal interstitial fibrosis due to unilateral ureteral obstruction in mice via TGFβ/Smad pathway (56). It has been reported that 25-O-methylalisol F, the main component of Alisma, protects EMT of rat renal proximal tubular epithelial cell lines through this pathway (57). The therapeutic effect of Radix Scrophulariae on SHR can be attributed to the suppression of the RAS through the inhibition of the extracellular regulated protein kinase 1/2, c-Jun N-terminal kinase and p38 MAPK pathways (58). Xin-Ji-Er-Kang can inhibit oxidative stress by affecting the RAS, and can improve renal injury after myocardial infarction in rats (59). In addition, all herbal medicines that contain flavonoids, terpenoids, saponins and alkaloids are able to inhibit the RAS (16). Among them, common herbs containing flavonoids are Scutellaria baicalensis, Flos cmysanthemi, Sambucus adnata wall, bud of Chinese Scholar tree, Equisetum spp, Chrysanthemum indicum L., Chamaecyparis obtusa, Orthosiphon stamineus and Tropaeolum Majus L. (60–62). Common herbs containing terpenoids are the surface layer and sclerotium of Poria cocos, Alismatis rhizome and Polyporus umbellatus (56,60,63). A common herb containing saponins is the ginseng root (64). Common herbs containing alkaloids are Gambirplant, leonurus, Ophora flavescens, S. subprostrata, S. alopecuroides and Uncaria rhynchophylla (60,65,66).

 Inhibition of sympathetic excitation

In patients with hypertension, the sympathetic adrenaline system is hyperactive from the central to the arterial walls. The synthesis and release of the neurotransmitter catecholamine increases, thus leading to renal arteriole contraction, and renal vascular resistance increases, thus affecting vascular remodeling (67,68). In addition, the catecholamine released by sympathetic nerves can directly act on proximal renal tubules, and increase sodium reabsorption, blood volume and blood pressure (69,70). Although it has not been demonstrated yet that the mechanism of herbal medicine in the treatment of hypertensive nephropathy involves the regulation of the sympathetic nervous system, numerous herbal medicines have been reported to be able to play a role in the inhibition of sympathetic nervous system in previous basic experiments and clinical trials.

Chrysanthemum plays a role in decreasing blood pressure by inhibiting the sympathetic nerve (50). Radix scrophulariae, by inhibiting sympathetic excitement, suppresses SHR, and ventricular remodeling occurs (58). Astragaloside IV can decrease norepinephrine levels in the blood of high-fat diet-induced obese rats and in kidney tissues, which indirectly demonstrates that Astragaloside IV has the effect of inhibiting sympathetic nerves (71). Guizhi decoction can inhibit the cholinergic transdifferentiation of sympathetic nerves, and improve the anatomical and functional denervation of sympathetic nerves (72). In addition, acupuncture, electroacupuncture and moxibustion can also regulate the sympathetic nervous system, although their mechanism of action is complex (73–75).

 Antioxidant stress and anti-inflammatory responses

Oxidative stress is caused by the imbalance of reactive oxygen species (ROS) and the antioxidant mechanism in the body. In hypertensive nephropathy, inflammatory damage is caused by the interaction of various cells such as macrophages and T lymphocytes, or inflammatory mediators or chemokines (13,76). These inflammatory cells secrete cytokines that can lead to endothelial dysfunction, which can aggravate and even lead to hypertension. Inflammatory reactions and oxidative stress play a common role and cause each other in hypertension-associated renal damage (77). Therefore, anti-oxidative stress and anti-inflammation can play a role in alleviating hypertensive nephropathy.

As the most widely used herb in cardiovascular diseases, Salvia miltiorrhiza can significantly improve SHR blood pressure, decrease ROS production and improve vascular remodeling (78). The flower of Coreopsis tinctoria Nutt. is widely used in the treatment of hypertension, diabetes, obesity and other diseases. It exerts anti-inflammatory effects through its antioxidant stress properties and its ability to inhibit tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and nuclear factor-κB (NF-κB) (79). Brazilian red propolis could alleviate hypertension and kidney injury in 5/6 renal ablation model rats through antioxidant stress (80). As an extract of Apocynum venetum, its polyphenols can improve the renal index of D-galactose-induced oxidative stress in mouse models (81). Tulbaghia violacea can improve NF-κB and TGF-β expression in Dahl salt-sensitive rat kidneys, and plays a role in lowering blood pressure and protecting renal function (82). Resveratrol, the main component of Veratrum nigrum L., has been demonstrated to have anti-ROS effects, and has the potential to lower blood pressure (83). As the main component of celery seeds, 3-n-butylphthalide plays a protective role in renal tubules through decreased stress, as well as the expression of pro-inflammatory cytokines and TGF-β1 in kidney tissues (84). Resveratrol, the main component of Veratrum nigrum L., has been demonstrated to have anti-ROS effects, and has the potential to lower blood pressure (85). Paeonol can effectively improve the blood pressure of spontaneously hypertensive rats, and its mechanism may be associated with reduction of blood viscosity, antioxidant stress and improvement of antioxidant capacity (86). Galangin, as the main extract of Alpinia officinarum hance, inhibits ROS as well as the mRNA expression of prostaglandin-endoperoxide synthase 2, TNF-α, IL-1β and IL-18, thus exerting a protective effect in rat renal epithelial cells (87). Icariin, as the main component of Epimedium brevicornu, can decrease the production of ROS by inhibiting the activity of NADPH oxidase, thus reducing the vasoconstriction effect of AngII-induced hypertension in rats (88). Natural antioxidants derived from food and herbal extracts such as tea polyphenols, curcumin and lycopene, have been widely used as complementary therapies to slow the progression of ESRD.

Jiang Ya Yi Shen granules exert their protective role by inhibiting NF-κB signaling-mediated micro-inflammatory cytokines, including IL-6, TNF-α and intercellular cell adhesion molecule-1 (ICAM-1), on SHR nephropathy (89). Tongxinluo can inhibit the effects of oxidative stress and improve SHR glomerular sclerosis (90). Ban Xia Bai Zhu Tian Ma decoction could inhibit IL-1, IL-6, TNF-α and inducible nitric oxide synthase (NOS) in SHR to improve the heart damage caused by hypertension (91). Qian Yang Yu Yin granules can also inhibit the influence of AngII on the NADPH oxidase 4-dependent pathway, thereby inhibiting the proliferation of human mesangial cells, and lowering the production of ROS and anti-inflammatory response (92). The heart-protecting musk pill, also called Shexiang Baoxin pill, can decrease TGF-β and ICAM-1, thus exerting an anti-inflammatory effect, and can be used to treat SHR nephropathy and to improve vascular remodeling (49,93). Xin-Ji-Er-Kang-induced NOS in high-salt induced hypertensive mice can improve the activity and oxidative stress, and alleviate vascular remodeling (94–96). Qingxuan Jiangya decoction can affect the TGF-β1/Smad signaling pathway to play a crucial role in improving renal interstitial fibrosis in SHR (97). In a previous study, Shenkang improved renal injury in mice with unilateral ureteral occlusion by acting on the TGF-β/Smad3, Sirtuin/forkhead box protein O and B-cell lymphoma-2-associated X protein pathways (98).

 Regulation of vasoactive substances and other mechanisms of endothelial cell protection

Hypertension can promote the synthesis of endothelial cells and the secretion of a variety of vasoactive substances. These substances maintain vascular tension and permeability, but can lead to vascular smooth muscle hypertrophy and hyperplasia. The sustained effect of blood pressure on vascular endothelial cells will result in endothelial cell damage (99,100). In addition, the increase in endogenous plasma NO synthase inhibitors in patients affects the decrease in NO synthesis by endothelial cells (101). The increase in ET-1, which can lead to vasoconstriction, eventually leads to enhanced vasoconstriction response and increased renal vascular resistance, and promotes the occurrence of vascular remodeling (37). Therefore, the best indicator of endothelial cell function is observation of the dynamic changes in vasoactive factors such as NO and ET-1.

Cirsium japonicum improves the cardiac effects of renal hypertension in 2-kidney 1-clip rats by increasing serum NO levels (102). Morinda citrifolia can significantly decrease blood pressure and 24-h urinary NO metabolite in SHR, and its juice extract can increase the phosphorylation of endothelial NOS in human umbilical vein endothelial cells, and promote the endothelial vasodilation of the aortic ring and NO products in rats (103). Zingiber officinale var. rubrum exerts a significant vascular relaxation effect in SHR. Its possible mechanism of vasodilatation includes the release of NO or transmembrane calcium channels (104). Curcumin can protect the renal kidney function of cadmium-induced renal damage in rats, and can play a protective role on renal injury caused by hyperuricemia or high-fructose intake, and one of the mechanisms is to increase the production of NO (105,106). Morin (also known as 3,5,7,2′,4′-pentahydroxyflavone) is widely present in fruits and vegetables such as almond, old fustic, Indian guava and Osage orange. This compound may play a strong role in vascular widening by NO, muscarinic receptors, β2-adrenegic receptors and calcium channels (107). Hydroxysafflor yellow A, the principal component of Carthamus tinctorius L., induces angiogenesis in rat mesenteric arteries by transient receptor potential vanilloid 4 (TRPV4) -dependent calcium influx in endothelial cells (108). A large number of clinical experiments showed that sodium tanshinone IIA sulfonate combined with angiotensin receptor blockers (ARBs) had a stronger effect on improving renal function in patients with primary hypertensive nephropathy compared with ARB monotherapy (109). Sodium tanshinone IIA sulfonate, the main ingredient in the herb Salvia miltiorrhiza, has been shown to protect vascular endothelial cells. In addition, the combination of caffeic acid and ferulic acid can dilate blood vessels and resist ET-1, while exerting a hypotensive effect through ester bonds and telmisartan (110). Qingxuan Jiangya decoction can prevent hypertension and improve vascular remodeling in SHR by lowering the serum ET-1 level and inhibiting the TGF-β1/Smad pathway (111). 17-Methoxyl-7-hydroxy-furanchalcone, as an active ingredient of Fordia cauliflora, was capable of improving cardiac reconstruction from hypertension in rats by regulating the eNOS-NO signaling pathway (112). The combination of Astragalus membranaceus and Salvia miltiorrhiza can improve IL-1β levels in SHR urine and eNOS levels in AngII-damaged human renal glomerular endothelial cells superfluid (113). San Cao decoction in network pharmacologic analysis may play a role in lowering blood pressure by regulating the PI3K-Akt-eNOS pathway (114).

 Improvement of obesity-associated factors

Metabolic disorder is also an important cause of hypertensive nephropathy (115). Obesity plays a greater role than blood pressure in the progression of hypertensive kidney disease (116). Obesity itself is a risk factor for high blood pressure. And in obese patients, renal dysfunction and associated increased sodium reabsorption in renal tubules can lead to hypertension (117). The compression of perirenal fat on the kidneys results in the activation of RAS (117). Chronic obesity may gradually amplify hypertension, leading to resistance to antihypertensive treatment. (117). Insulin resistance leads to the constriction of the extruded arterioles, thus leading to high glomerular pressure, hyperperfusion and hyperfiltration (118,119). These studies have demonstrated that obesity is closely associated with the incidence of hypertensive nephropathy. Herbal medicine has unique advantages in improving obesity. Astragaloside IV, as one of the main ingredients of Astragalus, is used to treat hypertension in high-fat diet-induced obese rats due to its anti-inflammatory effect and its ability to improve leptin resistance (71). Citrus paradisi and Ocimum sanctum infusions can decrease blood pressure and protect kidney function in obese rats (120).

A number of studies have shown that Chinese herbs can improve the effects of obesity on the kidneys of patients. Coptidis rhizoma can lower the blood lipid level and renal weight of fat-prone rats, and can improve urinary protein creatinine ratio and creatinine clearance rate in rats (121). The mechanism may be associated with the inhibition of the NLRP3 inflammasome (121). Through treatment of obesity-associated glomerulopathy in model rats with Tribulus terrestris L., it was found that the herb could decrease the body weight, blood pressure, serum cystatin C levels and migration of rats, as well as improve human endothelial cells migration, thus protecting renal function (80). Curcumin, as one of the most important components of turmeric, can improve body weight, abdominal fat index, urinary protein excretion and average glomerular diameter in mice, and can protect podocytes from leptin damage by blocking the Wnt/β-catenin pathway (122). At the formula level, Mai Tong Fang inhibits fat generation and triglyceride accumulation in 3T3-L1 adipocytes (123).

 Model of hypertensive nephropathy in herbal medicine research

In hypertensive nephropathy, herbal medicine has significant clinical efficacy in relieving proteinuria and controlling the progression of renal injury. However, the number of studies on the treatment of hypertensive nephropathy with Chinese herbal medicine is limited (Table SI). As aforementioned, certain compounds can control and alleviate diseases from multiple perspectives, and the Chinese herbs that contain such compounds have been listed. Subsequently, the present review tried to analyze the similarities of these plant medicines based on the theory of traditional Chinese medicine in an attempt to reach a conclusion. However, there are only few studies on this topic. Thus, the present review can only briefly discuss the summary of the application of herbal medicine in the basic research of hypertensive nephropathy.

In clinical research, the disease is often treated as one of the complications of hypertension, which has not received considerable attention. This is understandable, since the most effective way to control hypertensive nephropathy is to control blood pressure (124–126). Therefore, animal experimental models of hypertensive nephropathy are often used directly in hypertension models. Since hypertensive nephropathy is nephropathy caused by hypertension, modeling should ensure the presence of proteinuria without directly damaging the kidney. Therefore, the genetic hypertension model is the most common in such studies, while the renal hypertension model is the least desirable. Among these models, SHR was produced by inbreeding in Wistar rats with the highest blood pressure, and may progress to myocardial hypertrophy, heart failure, renal insufficiency and endothelium-dependent diastolic function impairment (127). Dahl salt-sensitive rats are SD rats on a high-salt diet (127). These rats showed myocardial hypertrophy, severe heart failure, hypertensive nephropathy, impaired endothelium-dependent diastolic function and other impairments (127–129). These animal models can reflect the pathogenesis of hypertensive nephropathy. Regarding cell models, previous studies have focused on endothelial cell injury, glomerular sclerosis and renal interstitial fibrosis (76). Therefore, the current common cell model involves the use of Ang II to interfere with endothelial cells and observe whether their function is abnormal, or to interfere with glomerular epithelial cells and renal tubular epithelial cells and observe whether they undergo EMT (54,130,131). The pathogenesis of hypertensive nephropathy is not only caused by an abnormal RAS, but is the result of multiple mechanisms. The best model would be extracting the serum of hypertensive animals or patients to incubate cells (132). However, no such model has been reported in the studies on herbal medicine for hypertensive nephropathy thus far. In future experimental cell research, such a model should be developed, so as to better reconstruct the patients' disease.

 Discussion

This review summarized three points. Firstly, the pathogenesis of hypertensive nephropathy was summarized. Secondly, herbal medicine studies based on these mechanisms were listed. Thirdly, the shortcomings of the current basic research on hypertensive nephropathy models and areas for improvement were discussed.

Hypertension nephropathy is a relatively complex mechanism of nephropathy. The basic pathogenesis of this disease includes renal hemodynamic changes and vascular remodeling, which are caused by various etiologies. At present, the treatment of hypertensive nephropathy in modern medicine is concentrated at a single site or approach, but the curative effect is not ideal. Different components of herbal medicine have obvious advantages in the treatment of hypertensive nephropathy. Previous studies on the efficacy and mechanism of herbal medicine in treating hypertensive nephropathy have suggested that herbal medicine plays an important role in improving renal perfusion, controlling vascular remodeling and delaying renal function progression. An interesting finding in these basic studies was that some herbs can act on two or three mechanisms at once. These experiments also provide evidence for the advantages of Chinese herbal medicine in the treatment of hypertensive nephropathy.

However, the clinical studies of herbal medicine on patients with hypertensive nephropathy are relatively scarce. Although basic research is essential in terms of the explanation of the mechanism, it is only used to observe the changes in a certain organ or even a certain type of cell, which makes the basic research itself somewhat static and one-sided, and it cannot observe the changes of patients dynamically and comprehensively as with clinical research. Therefore, basic research can only provide clues for the direction of clinical medicine, and cannot replace clinical research. Due to the lack of clinical data in this field, the content of this review has some limitations. In order to better promote traditional Chinese medicine, identify the efficacy of these herbs and explore their potential mechanisms, more clinical studies related to Chinese herbs are required in the future, as well as more well-designed, large-sample, long-term, randomized and controlled clinical trials to verify the efficacy and safety. With the in-depth study of herbal medicine, modern medicine will not only be able to treat hypertensive nephropathy, but also can make great progress in other disciplines.

 Supplementary Material Supporting Data Acknowledgements

Not applicable.

 Funding

This study was supported by grants from the National Key Research and Development Project (grant no. 2019YFC1709402), National Natural Science Foundation of China (grant nos. 81673907 and 81973793 awarded to LB), Natural Science Foundation of Beijing Municipality (grant no. 7182070 awarded to LB) and Beijing Municipal Administration of Hospitals Clinical Medicine Development of special funding support (grant no. XLMX201833 awarded to LB).

 Availability of data and materials

Not applicable.

 Authors' contributions

BL, HD and ZF provided valuable suggestions and guidance for writing this manuscript. ZD was responsible for collecting the majority of the material to be reviewed and for writing this manuscript. WL, YG and FL collected the rest of the material to be reviewed. ZZ, NZ and XD helped with writing the manuscript. QZ, XZ and JD were responsible for constructing Table 1. All authors read and approved the final manuscript.

 Ethics approval and consent to participate

Not applicable.

 Patient consent for publication

Not applicable.

 Competing interests

The authors declare that they have no competing interests.

 References SecciaTMCarocciaBCalòLAHypertensive nephropathy. Moving from classic to emerging pathogenetic mechanismsJ Hypertens35205212201710.1097/HJH.000000000000117027782909 HartPDBakrisGLHypertensive nephropathy: Prevention and treatment recommendationsExpert Opin Pharmacother1126752686201010.1517/14656566.2010.48561220718588 DamkjærMIsakssonGLStubbeJJensenBLAssersenKBiePRenal renin secretion as regulator of body fluid homeostasisPflugers Arch465153165201310.1007/s00424-012-1171-223096366 HuangQFHoshideSChengHMParkSParkCGChenCHKarioKWangJGCharacteristics On the Management of Hypertension in Asia-Morning Hypertension Discussion Group(COME Asia MHDG)Management of hypertension in patients with chronic kidney disease in AsiaCurr Hypertens Rev12181185201610.2174/157340211366616112211485427875953 LuXCrowleySDInflammation in salt-sensitive hypertension and renal damageCurr Hypertens Rep20103201810.1007/s11906-018-0903-x30377822 GuanZMakledMNInschoEWPurinoceptors, renal microvascular function and hypertensionPhysiol Res69353369202010.33549/physiolres.93446332301620 FreedmanBICohenAHHypertension-attributed nephropathy: What's in a name?Nat Rev Nephrol122736201610.1038/nrneph.2015.17226553514 KandasamyYWatsonDRuddDBiomarker of early glomerular injury in pre-eclampsiaHypertens Pregnancy34391399201510.3109/10641955.2015.106588326362027 MeierPAtherosclerotic renal artery stenosis: Update on management strategiesCurr Opin Cardiol26463471201110.1097/HCO.0b013e32834a6fe821799405 Rodriguez-IturbeBJohnsonRJThe role of renal microvascular disease and interstitial inflammation in salt-sensitive hypertensionHypertens Res33975980201010.1038/hr.2010.14820686485 TextorSCLermanLRenovascular hypertension and ischemic nephropathyAm J Hypertens2311591169201010.1038/ajh.2010.17420864945 UdaniSLazichIBakrisGLEpidemiology of hypertensive kidney diseaseNat Rev Nephrol71121201110.1038/nrneph.2010.15421079654 SunHJcurrent opinion for hypertension in renal fibrosisAdv Exp Med Biol11653747201910.1007/978-981-13-8871-2_331399960 XieXAtkinsELvJBennettANealBNinomiyaTWoodwardMMacMahonSTurnbullFHillisGSEffects of intensive blood pressure lowering on cardiovascular and renal outcomes: Updated systematic review and meta-analysisLancet387435443201610.1016/S0140-6736(15)00805-326559744 RomeroCACarreteroOATubule-vascular feedback in renal autoregulationAm J Physiol Renal Physiol316F1218F1226201910.1152/ajprenal.00381.201830838873 SatouRShaoWNavarLGRole of stimulated intrarenal angiotensinogen in hypertensionTher Adv Cardiovasc Dis9181190201510.1177/175394471558551225987608 LauWLHuisaBNFisherMthe cerebrovascular-chronic kidney disease connection: Perspectives and mechanismsTransl Stroke Res86776201710.1007/s12975-016-0499-x27628245 IhmCGHypertension in chronic glomerulonephritisElectrolyte Blood Press134145201510.5049/EBP.2015.13.2.4126848302 HughsonMDPuellesVGHoyWEDouglas-DentonRNMottSABertramJFHypertension, glomerular hypertrophy and nephrosclerosis: The effect of raceNephrol Dial Transplant2913991409201410.1093/ndt/gft48024327566 D'EliaJABaylissGGleasonREWeinrauchLACardiovascular-renal complications and the possible role of plasminogen activator inhibitor: A reviewClin Kidney J9705712201610.1093/ckj/sfw08027679717 SimeoniMArmeniASummariaCCerantonioAFuianoGCurrent evidence on the use of anti-RAAS agents in congenital or acquired solitary kidneyRen Fail39660670201710.1080/0886022X.2017.136184028805480 CampeseVMMitraNSandeeDHypertension in renal parenchymal disease: Why is it so resistant to treatment?Kidney Int69967973200610.1038/sj.ki.500017716528245 HeymanSNKhamaisiMRosenSRosenbergerCRenal parenchymal hypoxia, hypoxia response and the progression of chronic kidney diseaseAm J Nephrol289981006200810.1159/00014607518635927 LermanLOTextorSCGrandeJPMechanisms of tissue injury in renal artery stenosis: Ischemia and beyondProg Cardiovasc Dis52196203200910.1016/j.pcad.2009.09.00219917330 ZengYWangXXieFZhengZIschemia-induced glomerular parietal epithelial cells hyperplasia: Commonly misdiagnosed cellular crescent in renal biopsyPathol Res Pract213982986201710.1016/j.prp.2017.04.00628595914 NicolosiPATombettiEMaugeriNRovere-QueriniPBrunelliSManfrediAAVascular remodelling and mesenchymal transition in systemic sclerosisStem Cells Int20164636859201610.1155/2016/463685927069480 Rodriguez-IturbeBPonsHJohnsonRJRole of the immune system in hypertensionPhysiol Rev9711271164201710.1152/physrev.00031.201628566539 FrameAAWainfordRDMechanisms of altered renal sodium handling in age-related hypertensionAm J Physiol Renal Physiol315F1F6201810.1152/ajprenal.00594.201729442548 ZhangCBoozGWYuQHeXWangSFanFConflicting roles of 20-HETE in hypertension and renal end organ damageEur J Pharmacol833190200201810.1016/j.ejphar.2018.06.01029886242 Mendoza-TorresEOyarzúnAMondaca-RuffDAzocarACastroPFJalilJEChiongMLavanderoSOcaranzaMPACE2 and vasoactive peptides: Novel players in cardiovascular/renal remodeling and hypertensionTher Adv Cardiovasc Dis9217237201510.1177/175394471559762326275770 LaurentSBoutouyriePThe structural factor of hypertension: Large and small artery alterationsCirc Res11610071021201510.1161/CIRCRESAHA.116.30359625767286 MiyagawaKEmotoNCurrent state of endothelin receptor antagonism in hypertension and pulmonary hypertensionTher Adv Cardiovasc Dis8202216201410.1177/175394471454151124990369 PovlsenALGrimmDWehlandMInfangerMKrügerMThe vasoactive mas receptor in essential hypertensionJ Clin Med9267202010.3390/jcm9010267 TracyRERenal vasculature in essential hypertension: A review of some contrarian evidenceContrib Nephrol169327336201110.1159/00031490821252530 BrownIAMDiederichLGoodMEDeLalioLJMurphySACortese-KrottMMHallJLLeTHIsaksonBEVascular smooth muscle remodeling in conductive and resistance arteries in hypertensionArterioscler Thromb Vasc Biol3819691985201810.1161/ATVBAHA.118.31122930354262 LiQYounJYCaiHMechanisms and consequences of endothelial nitric oxide synthase dysfunction in hypertensionJ Hypertens3311281136201510.1097/HJH.000000000000058725882860 XuMLuYPHasanAAHocherBPlasma ET-1 concentrations are elevated in patients with hypertension-meta-analysis of clinical studiesKidney Blood Press Res42304313201710.1159/00047757228531898 VersmissenJMirabito ColafellaKMKoolenSLWDanserAHJVascular cardio-oncology: Vascular endothelial growth factor inhibitors and hypertensionCardiovasc Res115904914201910.1093/cvr/cvz02230726882 WuJAgborLNFangSMukohdaMNairARNakagawaPSharmaAMorganDAGrobeJLRahmouniKFailure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertensionCardiovasc Res117308319202110.1093/cvr/cvaa14732428209 HillGSHypertensive nephrosclerosisCurr Opin Nephrol Hypertens17266270200810.1097/MNH.0b013e3282f88a1f18408477 ZhangLYangLShergisJZhangLZhangALGuoXQinXJohnsonDLiuXLuCChinese herbal medicine for diabetic kidney disease: A systematic review and meta-analysis of randomised placebo-controlled trialsBMJ Open9e025653201910.1136/bmjopen-2018-02565331048437 RenWLiaoJChenJLiZHuangLThe effect of Chinese herbal medicine combined with western medicine on vascular endothelial function for patients with hypertension: Protocol for a systematic review and meta-analysisMedicine (Baltimore)98e18134201910.1097/MD.000000000001813431804323 WangJQinTChenJLiYWangLHuangHLiJHyperuricemia and risk of incident hypertension: A systematic review and meta-analysis of observational studiesPLoS One9e114259201410.1371/journal.pone.011425925437867 GaoXPeleliMZollbrechtCPatzakAPerssonAECarlströmMAdenosine A1 receptor-dependent and independent pathways in modulating renal vascular responses to angiotensin IIActa Physiol (Oxf)213268276201510.1111/apha.1239925251152 PojogaLHYaoTMOpsasnickLASiddiquiWTReslanOMAdlerGKWilliamsGHKhalilRACooperative role of mineralocorticoid receptor and caveolin-1 in regulating the vascular response to low nitric oxide-high angiotensin II-induced cardiovascular injuryJ Pharmacol Exp Ther3553247201510.1124/jpet.115.22604326183312 YuDShiMBaoJYuXLiYLiuWGenipin ameliorates hypertension-induced renal damage via the angiotensin II-TLR/MyD88/MAPK pathwayFitoterapia112244253201610.1016/j.fitote.2016.06.01027343367 ZhangSFMaoXJJiangWMFangZYQian Yang Yu Yin Granule protects against hypertension-induced renal injury by epigenetic mechanism linked to nicotinamide N-methyltransferase (NNMT) expressionJ Ethnopharmacol255112738202010.1016/j.jep.2020.11273832147479 HanLMaYQinJGLiLNGaoYSZhangXYGuoYSongLMLuoYNChiXYThe renal protective effect of Jiangya tongluo formula, through regulation of adrenomedullin and angiotensin II, in rats with hypertensive nephrosclerosisEvid Based Complement Alternat Med2015428106201510.1155/2015/42810626557147 TianDLingSChenGLiYLiuJFeridMBianKHypertensive nephropathy treatment by heart-protecting musk pill: A study of anti-inflammatory therapy for target organ damage of hypertensionInt J Gen Med4131139201121475627 ChenYHLeiSSLiBLuoRHeXWangYZZhouFCLvGYChenSHSystematic understanding of the mechanisms of flos chrysanthemi indici-mediated effects on hypertension via computational target fishingComb Chem High Throughput Screen2392110202010.2174/138620732366620012210541031969096 LimónRIPeñasEMartínez-VillaluengaCFriasJRole of elicitation on the health-promoting properties of kidney bean sproutsLWT Food Sci Technol56328334201410.1016/j.lwt.2013.12.014 ChenHWangMCChenYYChenLWangYNVaziriNDMiaoHZhaoYYAlisol B 23-acetate attenuates CKD progression by regulating the renin-angiotensin system and gut-kidney axisTher Adv Chronic Dis112040622320920025202010.1177/204062232092002532547719 ChenLChenDQWangMLiuDChenHDouFVaziriNDZhaoYYRole of RAS/Wnt/β-catenin axis activation in the pathogenesis of podocyte injury and tubulo-interstitial nephropathyChem Biol Interact2735672201710.1016/j.cbi.2017.05.02528578904 WangMChenDQWangMCChenHChenLLiuDZhaoHZhaoYYPoricoic acid ZA, a novel RAS inhibitor, attenuates tubulo-interstitial fibrosis and podocyte injury by inhibiting TGF-β/Smad signaling pathwayPhytomedicine36243253201710.1016/j.phymed.2017.10.00829157821 WangMChenDQChenLLiuDZhaoHZhangZHVaziriNDGuoYZhaoYYCaoGNovel RAS inhibitors poricoic acid ZG and poricoic acid ZH attenuate renal fibrosis via a Wnt/β-catenin pathway and targeted phosphorylation of Smad3 signalingJ Agric Food Chem6618281842201810.1021/acs.jafc.8b0009929383936 WangMChenDQChenLCaoGZhaoHLiuDVaziriNDGuoYZhaoYYNovel inhibitors of the cellular renin-angiotensin system components, poricoic acids, target Smad3 phosphorylation and Wnt/β-catenin pathway against renal fibrosisBr J Pharmacol17526892708201810.1111/bph.1433329679507 ChenHYangTWangMCChenDQYangYZhaoYYNovel RAS inhibitor 25-O-methylalisol F attenuates epithelial-to-mesenchymal transition and tubulo-interstitial fibrosis by selectively inhibiting TGF-β-mediated Smad3 phosphorylationPhytomedicine42207218201810.1016/j.phymed.2018.03.03429655688 ZhangCCGuWLWuXMLiYMChenCXHuangXYActive components from Radix scrophulariae inhibits the ventricular remodeling induced by hypertension in ratsSpringerplus5358201610.1186/s40064-016-1985-z27066371 LianFZChengPRuanCSLingXXWangXYPanMChenMLShenAZGaoSXin-Ji-Er-Kang ameliorates kidney injury following myocardial infarction by inhibiting oxidative stress via Nrf2/HO-1 pathway in ratsBiomed Pharmacother117109124201910.1016/j.biopha.2019.10912431228798 YangTChenYYLiuJRZhaoHVaziriNDGuoYZhaoYYNatural products against renin-angiotensin system for antifibrosis therapyEur J Med Chem179623633201910.1016/j.ejmech.2019.06.09131279295 DengYFAlukoREJinQZhangYYuanLJInhibitory activities of baicalin against renin and angiotensin-converting enzymePharm Biol50401406201210.3109/13880209.2011.60807622136493 LvGYZhangYPGaoJLYuJJLeiJZhangZRLiBZhanRJChenSHCombined antihypertensive effect of luteolin and buddleoside enriched extracts in spontaneously hypertensive ratsJ Ethnopharmacol150507513201310.1016/j.jep.2013.08.05824080032 ZhaoYYLiHTFengYLBaiXLinRCUrinary metabonomic study of the surface layer of Poria cocos as an effective treatment for chronic renal injury in ratsJ Ethnopharmacol148403410201310.1016/j.jep.2013.04.01823612421 ZhengXWangSZouXJingYYangRLiSWangFGinsenoside Rb1 improves cardiac function and remodeling in heart failureExp Anim66217228201710.1538/expanim.16-012128367863 KaiserSCarvalhoÂRPittolVDietrichFManicaFMachadoMMde OliveiraLFOliveira BattastiniAMOrtegaGGGenotoxicity and cytotoxicity of oxindole alkaloids from Uncaria tomentosa (cat's claw): Chemotype relevanceJ Ethnopharmacol1899098201610.1016/j.jep.2016.05.02627180878 ZhangRHLiuZKYangDSZhangXJSunHDXiaoWLPhytochemistry and pharmacology of the genus leonurus: The herb to benefit the mothers and morePhytochemistry147167183201810.1016/j.phytochem.2017.12.01629335190 RossiGPSecciaTMBartonMDanserAHJde LeeuwPWDhaunNRizzoniDRossignolPRuilopeLMvan den MeirackerAHEndothelial factors in the pathogenesis and treatment of chronic kidney disease part I: General mechanisms: A joint consensus statement from the European society of hypertension working group on endothelin and endothelial factors and the Japanese society of hypertensionJ Hypertens36451461201810.1097/HJH.000000000000159929120962 BrusilovskayaKKönigshoferPSchwablPReibergerTVascular targets for the treatment of portal hypertensionSemin Liver Dis39483501201910.1055/s-0039-169311531315135 WestfallTCMacarthurHBykuMYangCLMurrayJInteractions of neuropeptide y, catecholamines, and angiotensin at the vascular neuroeffector junctionAdv Pharmacol68115139201310.1016/B978-0-12-411512-5.00006-324054142 ZhuXZhouZZhangQCaiWZhouYSunHQiuLVaccarin administration ameliorates hypertension and cardiovascular remodeling in renovascular hypertensive ratsJ Cell Biochem119926937201810.1002/jcb.2625828681939 JiangPMaDWangXWangYBiYYangJWangXLiXAstragaloside IV prevents obesity-associated hypertension by improving pro-inflammatory reaction and leptin resistanceMol Cells41244255201829562733 WangYCMaDFJiangPZhangYMZhouGFYangJLLiZYLiXGuizhi decoction () inhibits cholinergic transdifferentiation by regulating imbalance of NGF and LIF in salt-sensitive hypertensive heart failure ratsChin J Integr Med26188196202010.1007/s11655-019-2706-631111424 XiongWHeFFYouRYXiongJWangYMZhangCMengXFSuHAcupuncture application in chronic kidney disease and its potential mechanismsAm J Chin Med4611691185201810.1142/S0192415X1850061130286626 PaternoJCBergamaschiCTCamposRRHigaEMSoaresMFSchorNFreireAOTeixeiraVPElectroacupuncture and moxibustion decrease renal sympathetic nerve activity and retard progression of renal disease in ratsKidney Blood Press Res35355364201210.1159/00033609522473039 YangJWYeYWangXRLiFXiaoLYShiGXLiuCZAcupuncture attenuates renal sympathetic activity and blood pressure via beta-adrenergic receptors in spontaneously hypertensive ratsNeural Plast20178696402201710.1155/2017/869640228270938 MennuniSRubattuSPierelliGTocciGFofiCVolpeMHypertension and kidneys: Unraveling complex molecular mechanisms underlying hypertensive renal damageJ Hum Hypertens287479201410.1038/jhh.2013.5523803592 CrowleySDThe cooperative roles of inflammation and oxidative stress in the pathogenesis of hypertensionAntioxid Redox Signal20102120201410.1089/ars.2013.525823472597 ZhangJAnSJFuJQLiuPShaoTMLiMLiXJiaoZChaiXQMixed aqueous extract of Salvia miltiorrhiza reduces blood pressure through inhibition of vascular remodelling and oxidative stress in spontaneously hypertensive ratsCell Physiol Biochem40347360201610.1159/00045255027866193 LiYHuangCFuWZhangHLaoYZhouHTanHXuHScreening of the active fractions from the Coreopsis tinctoria nutt. Flower on diabetic endothelial protection and determination of the underlying mechanismJ Ethnopharmacol253112645202010.1016/j.jep.2020.11264532045684 TelesFda SilvaTMda Cruz JúniorFPHonoratoVHde Oliveira CostaHBarbosaAPde OliveiraSGPorfírioZLibórioABBorgesRLFanelliCBrazilian red propolis attenuates hypertension and renal damage in 5/6 renal ablation modelPLoS One10e0116535201510.1371/journal.pone.011653525607548 GuoHKuangZZhangJZhaoXPuPYanJThe preventive effect of Apocynum venetum polyphenols on D-galactose-induced oxidative stress in miceExp Ther Med19557568202031897099 MoodleyKNaidooYMackrajIEffects of Tulbaghia violacea Harv. (Alliaceae) rhizome methanolic extract on kidney function and morphology in Dahl salt-sensitive ratsJ Ethnopharmacol15511941203201410.1016/j.jep.2014.07.00325017374 HamzaSMDyckJRSystemic and renal oxidative stress in the pathogenesis of hypertension: Modulation of long-term control of arterial blood pressure by resveratrolFront Physiol5292201410.3389/fphys.2014.0029225140155 ZhuJZhangYYangCProtective effect of 3-n-butylphthalide against hypertensive nephropathy in spontaneously hypertensive ratsMol Med Rep1114481454201510.3892/mmr.2014.279125352064 LinFHuangXXingFXuLZhangWChenZKeXSongYZengZSemen brassicae reduces thoracic aortic remodeling, inflammation, and oxidative damage in spontaneously hypertensive ratsBiomed Pharmacother129110400202010.1016/j.biopha.2020.11040032570115 GaiZWangZZhangLMaJZhuQPaeonol protects against hypertension in spontaneously hypertensive rats by restoring vascular endotheliumBiosci Biotechnol Biochem8319921999201910.1080/09168451.2019.164820331362597 LuHYaoHZouRChenXXuHGalangin suppresses renal inflammation via the inhibition of NF-κB, PI3K/AKT and NLRP3 in uric acid treated NRK-52E tubular epithelial cellsBiomed Res Int20193018357201910.1155/2019/301835731240210 DongHMingSFangJLiYLiuLIcariin ameliorates angiotensin II-induced cerebrovascular remodeling by inhibiting Nox2-containing NADPH oxidase activationHum Cell322230201910.1007/s13577-018-0220-330386989 YanDYueBQianMZhaoLZhangZQianHYanSQianYFangZJYYS granule mitigates renal injury in clinic and in spontaneously hypertensive rats by inhibiting NF-κB signaling-mediated microinflammationEvid Based Complement Alternat Med20188472963201810.1155/2018/847296330598687 LuoWMKongJGongYLiuXQYangRXZhaoYXTongxinluo protects against hypertensive kidney injury in spontaneously-hypertensive rats by inhibiting oxidative stress and activating forkhead box o1 signalingPLoS One10e0145130201510.1371/journal.pone.014513026673167 JiangJHuangDLiYGanZLiHLiXBianKKeYHeart protection by herb formula BanXia BaiZhu TianMa decoction in spontaneously hypertensive ratsEvid Based Complement Alternat Med20195612929201910.1155/2019/561292931827552 DingKWangYJiangWZhangYYinHFangZQian Yang Yu Yin Granule-containing serum inhibits angiotensin II-induced proliferation, reactive oxygen species production, and inflammation in human mesangial cells via an NADPH oxidase 4-dependent pathwayBMC Complement Altern Med1581201510.1186/s12906-015-0619-225886843 LuLSunXChenCQinYGuoXShexiang baoxin pill, derived from the traditional Chinese medicine, provides protective roles against cardiovascular diseasesFront Pharmacol91161201810.3389/fphar.2018.0116130487746 WangXYHuangGYLianFZPanMRuanCSLingXXChenMLShenAZGaoSProtective effect of Xin-Ji-Er-Kang on cardiovascular remodeling in high-salt induced hypertensive mice: Role ofoxidative stress and endothelial dysfunctionBiomed Pharmacother115108937201910.1016/j.biopha.2019.10893731078040 GuoKLanCZYuTTHuangLLWangXHPanCGaoSEffects of Xin-Ji-Er-Kang formula on 2K1C-induced hypertension and cardiovascular remodeling in ratsJ Ethnopharmacol15512271235201410.1016/j.jep.2014.07.00625063306 YuTTGuoKChenHCLanCZWangJHuangLLWangXHZhangZGaoSEffects of traditional Chinese medicine Xin-Ji-Er-Kang formula on 2K1C hypertensive rats: Role of oxidative stress and endothelial dysfunctionBMC Complement Altern Med13173201310.1186/1472-6882-13-17323849603 LiuWLinSCaiQZhangLShenAChenYPengJQingxuan Jiangya decoction mitigates renal interstitial fibrosis in spontaneously hypertensive rats by regulating transforming growth factor-β1/Smad signaling pathwayEvid Based Complement Alternat Med20171576328201710.1155/2017/157632829441112 QinTWuLHuaQSongZPanYLiuTPrediction of the mechanisms of action of Shenkang in chronic kidney disease: A network pharmacology study and experimental validationJ Ethnopharmacol246112128202010.1016/j.jep.2019.11212831386888 TianXLLiYEndothelial cell senescence and age-related vascular diseasesJ Genet Genomics41485495201410.1016/j.jgg.2014.08.00125269674 ReginaCPanattaECandiEMelinoGAmelioIBalistreriCRAnnicchiarico-PetruzzelliMDi DanieleNRuvoloGVascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseasesMech Ageing Dev1591421201610.1016/j.mad.2016.05.00327155208 LankhorstSKappersMHvan EschJHDanserAHvan den MeirackerAHHypertension during vascular endothelial growth factor inhibition: Focus on nitric oxide, endothelin-1, and oxidative stressAntioxid Redox Signal20135145201410.1089/ars.2013.524423458507 YangXShaoHChenYDingNYangATianJJiangYLiGJiangYIn renal hypertension, Cirsium japonicum strengthens cardiac function via the intermedin/nitric oxide pathwayBiomed Pharmacother101787791201810.1016/j.biopha.2018.02.12629525674 YoshitomiHZhouJNishigakiTLiWLiuTWuLGaoMMorinda citrifolia (Noni) fruit juice promotes vascular endothelium function in hypertension via glucagon-like peptide-1 receptor-CaMKKβ-AMPK-eNOS pathwayPhytother Res3423412350202010.1002/ptr.668532298014 RazaliNDewaAAsmawiMZMohamedNManshorNMMechanisms underlying the vascular relaxation activities of Zingiber officinale var. rubrum in thoracic aorta of spontaneously hypertensive ratsJ Integr Med184658202010.1016/j.joim.2019.12.00331882255 AkinyemiAJOnyebuekeNFaboyaOAOnikanniSAFadakaAOlayideICurcumin inhibits adenosine deaminase and arginase activities in cadmium-induced renal toxicity in rat kidneyJ Food Drug Anal25438446201710.1016/j.jfda.2016.06.00428911688 ZhangDMLiYCXuDDingXQKongLDProtection of curcumin against fructose-induced hyperuricaemia and renal endothelial dysfunction involves NO-mediated JAK-STAT signalling in ratsFood Chem13421842193201210.1016/j.foodchem.2012.04.02623442673 TewWYTanCSAsmawiMZYamMFUnderlying mechanism of vasorelaxant effect exerted by 3,5,7,2′,4′-pentahydroxyflavone in rats aortic ringEur J Pharmacol880173123202010.1016/j.ejphar.2020.17312332335091 YangJWangRChengXQuHQiJLiDXingYBaiYZhengXThe vascular dilatation induced by Hydroxysafflor yellow A (HSYA) on rat mesenteric artery through TRPV4-dependent calcium influx in endothelial cellsJ Ethnopharmacol256112790202010.1016/j.jep.2020.11279032234595 XuJZhangCShiXLiJLiuMJiangWFangZEfficacy and safety of sodium tanshinone IIA sulfonate injection on hypertensive nephropathy: A systematic review and meta-analysisFront Pharmacol101542201910.3389/fphar.2019.0154231920681 LiPPengYMaQLiZZhangXStudy on the formation of antihypertensive twin drugs by caffeic acid and ferulic acid with telmisartanDrug Des Devel Ther14977992202010.2147/DDDT.S22570532184567 HeFChuJFChenHWLinWLinSChenYQPengJChenKJQingxuan Jiangya decoction () prevents blood pressure elevation and ameliorates vascular structural remodeling via modulating TGF-β 1/Smad pathway in spontaneously hypertensive ratsChin J Integr Med26180187202010.1007/s11655-019-2705-731883057 YeFHeJWuXXieJChenHTangXLaiZHuangRHuangJThe regulatory mechanisms of Yulangsan MHBFC reversing cardiac remodeling in rats based on eNOS-NO signaling pathwayBiomed Pharmacother117109141201910.1016/j.biopha.2019.10914131228800 LiWJiangYHWangYZhaoMHouGJHuHZZhouLProtective effects of combination of radix astragali and radix salviae miltiorrhizae on kidney of spontaneously hypertensive rats and renal intrinsic cellsChin J Integr Med264653202010.1007/s11655-019-3071-131388973 MaCZhaiCXuTLuFZhangSLiCWangQChengFWangXA systems pharmacology-based study of the molecular mechanisms of San Cao decoction for treating hypertensionEvid Based Complement Alternat Med20193171420201910.1155/2019/317142031354853 TanakaMItohHHypertension as a metabolic disorder and the novel role of the gutCurr Hypertens Rep2163201910.1007/s11906-019-0964-531236708 HallJEdo CarmoJMda SilvaAAWangZHallMEObesity, kidney dysfunction and hypertension: Mechanistic linksNat Rev Nephrol15367385201910.1038/s41581-019-0145-431015582 BellDSTreatment of diabetic hypertensionDiabetes Obes Metab11433444200910.1111/j.1463-1326.2008.00983.x19236440 BusijaDWMillerAWKatakamPErdösBInsulin resistance and associated dysfunction of resistance vessels and arterial hypertensionMinerva Med96223232200516179890 EringaECBakkerWvan HinsberghVWParacrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissueVascul Pharmacol56204209201210.1016/j.vph.2012.02.00322366250 Gamboa-GómezCPérez-RamírezIFGonzález-GallardoAGallegos-CoronaMAIbarra-AlvaradoCReynoso-CamachoREffect of Citrus paradisi and Ocimum sanctum infusions on blood pressure regulation and its association with renal alterations in obese ratsJ Food Biochem40345357201610.1111/jfbc.12216 RenYWangDLuFZouXXuLWangKHuangWSuHZhangCGaoYDongHCoptidis rhizoma inhibits NLRP3 inflammasome activation and alleviates renal damage in early obesity-related glomerulopathyPhytomedicine495265201810.1016/j.phymed.2018.05.01930217262 LiuBLChenYPChengHWangYYRuiHLYangMDongHRHanDNDongJThe protective effects of curcumin on obesity-related glomerulopathy are associated with inhibition of Wnt/β-catenin signaling activation in podocytesEvid Based Complement Alternat Med2015827472201510.1155/2015/82747226539236 MaLHuangLPeiHLiuZXieCLeiLChenXYeHPengAChenLPharmacological effects of the water fraction of key components in the traditional Chinese prescription Mai Tong Fang on 3T3-L1 adipocytes and ob/ob diabetic miceMolecules191468714698201410.3390/molecules19091468725230123 BasileJTothPAngiotensin receptor blockers: Role in hypertension management, cardiovascular risk reduction, and nephropathySouth Med J102(10 Suppl)S1S12200910.1097/SMJ.0b013e3181ba0d8a19834426 PirkleJLFreedmanBIHypertension and chronic kidney disease: Controversies in pathogenesis and treatmentMinerva Urol Nefrol653750201323538309 YangCWangHZhaoXMatsushitaKCoreshJZhangLZhaoMHCKD in China: Evolving spectrum and public health implicationsAm J Kidney Dis76258264202010.1053/j.ajkd.2019.05.03231492486 LeongXFNgCYJaarinKAnimal models in cardiovascular research: Hypertension and atherosclerosisBiomed Res Int2015528757201510.1155/2015/52875726064920 Meili-ButzSBühlerKJohnDBuserPValeWWPetersonKLBrinkMDieterleTAcute effects of urocortin 2 on cardiac function and propensity for arrhythmias in an animal model of hypertension-induced left ventricular hypertrophy and heart failureEur J Heart Fail12797804201010.1093/eurjhf/hfq05420388649 LiuMLSongHXTianXXLiuYXLiuDHouZWLiJYYanCHHanYLRecombinant cellular repressor of E1A-stimulated genes protects against renal fibrosis in Dahl salt-sensitive ratsAm J Nephrol51401410202010.1159/00050641132320986 LuQMaZDingYBedaridaTChenLXieZSongPZouMHCirculating miR-103a-3p contributes to angiotensin II-induced renal inflammation and fibrosis via a SNRK/NF-κB/p65 regulatory axisNat Commun102145201910.1038/s41467-019-10116-031086184 HanWQXuLTangXFChenWDWuYJGaoPJMembrane rafts-redox signalling pathway contributes to renal fibrosis via modulation of the renal tubular epithelial-mesenchymal transitionJ Physiol59636033616201810.1113/JP27595229863758 SuYDengXMaRDongZWangFShiJThe Exposure of phosphatidylserine influences procoagulant activity in retinal vein occlusion by microparticles, blood cells, and endotheliumOxid Med Cell Longev20183658476201810.1155/2018/365847630057675

Basic experimental studies on herbal medicine prescriptions.

Composition Animal Cell Mechanisms (Refs)
Polygoni Multiflori Radix, Herba Bidentis Bipinnatae, Corni Fructus – 293T cells Suppression of renin-angiotensin system (44)
Scrophulariae Radix, Alismatis Rhizoma, Cyathulae Radix – Human mesangial cells Antioxidant stress and anti-inflammatory responses (89)
Bidens pilosa Linn, Cornus officinalis Sieb. et Zucc, Fallopia multiflora (Tunb.) Harald., Scrophu laria ningpoensis Hemsl., Cyathula officinalis Kuan, Alisma plantago-aquatica Linn. SHR – Antioxidant stress and anti-inflammatory responses (86)
Nacre, Cassia occidentalis, Safflower, Salvia miltiorrhiza, Chrysanthemum SHR – Suppression of renin-angiotensin system (45)
Artificial Mouchus, Cortex Cinnamomi, Calculus Bovis Artifactus, Styrax, Radix Ginseng, Syntheticum, Venenum Bufonis SHR – Suppression of renin-angiotensin system; antioxidant stress and Borneolum anti-inflammatory responses (46)