Icariin improves acute kidney injury and proteinuria in a rat model of pregnancy‑induced hypertension

Zhang,Wenyu; Yuan,Wei; Xu,Ning; Li,Jinping; Chang,Wenxiu

doi:10.3892/mmr.2017.7513

Icariin improves acute kidney injury and proteinuria in a rat model of pregnancy‑induced hypertension

Authors:
- Wenyu Zhang
- Wei Yuan
- Ning Xu
- Jinping Li
- Wenxiu Chang
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Affiliations: Department of Nephrology, Tianjin First Central Hospital, Tianjin 300192, P.R. China
Published online on: September 19, 2017 https://doi.org/10.3892/mmr.2017.7513
Pages: 7398-7404
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Icariin has previously been demonstrated to attenuate hyperglycemia‑induced renal injury, however the renoprotective effects of icariin in a rat model of pregnancy‑induced hypertension (PIH) remain to be elucidated. The present study aimed to investigate the effect of icariin on PIH‑induced acute kidney injury (AKI) and proteinuria. Following 18 days of icariin treatment between day 1 and day 18 of gestation, which was combined with NG‑nitro‑L‑arginine methyl ester (L‑NAME) treatment between day 12 and day 18 of gestation to induce PIH, the 24 h urine protein level, blood urea nitrogen and serum creatinine were measured by using the Coomassie Brilliant Blue method, a commercial enzymatic kit and the picric acid method, respectively. Renal tissues were collected at day 18 of gestation for hematoxylin and eosin staining and immunohistochemistry. The mRNA expression of AGT and protein expression of angiotensin II (Ang II) in the kidneys of control and PIH rats was investigated by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively, to determine the effect of icariin on components of the renin‑angiotensin system. The results demonstrated that L‑NAME treatment in pregnant rats resulted in significant increases in systolic blood pressure (SBP) and diastolic blood pressure, in addition to the induction of severe proteinuria. The significant increase in SBP and proteinuria in PIH rats was prevented by icariin. L‑NAME‑induced AKI resulted in profound renal histological alterations, including mesangial expansion and glomerular lesions. L‑NAME administration exerted a marked decrease in the mRNA and protein expression levels of nephrin in the kidneys from PIH rats compared with control group. Furthermore, upregulation of circulating and renal Ang II levels in PIH rats was observed. However, icariin treatment significantly reversed the L‑NAME‑induced downregulation of nephrin and upregulation of circulating and renal Ang II levels in PIH rats. These results demonstrated that icariin administration improved urinary protein excretion levels and renal tissue damage in PIH rats, and the underlying mechanism was mediated in part, via upregulation of nephrin expression and downregulation of Ang II.

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1	Veerbeek JH, Hermes W, Breimer AY, van Rijn BB, Koenen SV, Mol BW, Franx A, de Groot CJ and Koster MP: Cardiovascular disease risk factors after early-onset preeclampsia, late-onset preeclampsia and pregnancy-induced hypertension. Hypertension. 65:600–606. 2015. View Article : Google Scholar : PubMed/NCBI
2	Shortliffe LM, Hammam O, Han X, Kouba E, Tsao PS and Wang B: Dietary fructose in pregnancy induces hyperglycemia, hypertension, and pathologic kidney and liver changes in a rodent model. Pregnancy Hypertens. 5:308–314. 2015.PubMed/NCBI
3	Kendrick J, Sharma S, Holmen J, Palit S, Nuccio E and Chonchol M: Kidney disease and maternal and fetal outcomes in pregnancy. Am J Kidney Dis. 66:55–59. 2015. View Article : Google Scholar : PubMed/NCBI
4	Liu YM, Bao HD, Jiang ZZ, Huang YJ and Wang NS: Pregnancy-related acute kidney injury and a review of the literature in China. Intern Med. 54:1695–1703. 2015. View Article : Google Scholar : PubMed/NCBI
5	Carty DM, Delles C and Dominiczak AF: Preeclampsia and future maternal health. J Hypertens. 28:1349–1355. 2010. View Article : Google Scholar : PubMed/NCBI
6	Haase N, Golic M, Herse F, Rugor J, Linz D, Solano ME, Müller DN and Dechend R: Relaxin treatment in an Ang-II-based transgenic preeclamptic-rat model. PLoS One. 11:e01507432016. View Article : Google Scholar : PubMed/NCBI
7	Fan C, Yang Y, Liu Y, Jiang S, Di S, Hu W, Ma Z, Li T, Zhu Y and Xin Z: Icariin displays anticancer activity against human esophageal cancer cells via regulating endoplasmic reticulum stress-mediated apoptotic signaling. Sci Rep. 6:211452016. View Article : Google Scholar : PubMed/NCBI
8	Wang J, Tao Y, Ping Z, Zhang W, Hu X, Wang Y, Wang L, Shi J, Wu X and Yang H: Icariin attenuates titanium-particle inhibition of bone formation by activating the Wnt/β-catenin signaling pathway in vivo and in vitro. Sci Rep. 6:238272016. View Article : Google Scholar : PubMed/NCBI
9	Zhang G, Qin L and Shi Y: Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: A 24-month randomized, double-blind and placebo-controlled trial. J Bone Miner Res. 22:1072–1079. 2007. View Article : Google Scholar : PubMed/NCBI
10	Xiao-Hong D, Chang-Qin X, Jian-Hua H, Wen-Jiang Z and Bing S: Icariin delays homocysteine-induced endothelial cellular senescence involving activation of the PI3K/AKT-eNOS signaling pathway. Pharm Biol. 51:433–440. 2013. View Article : Google Scholar : PubMed/NCBI
11	Ma P, Zhang S, Su X, Qiu G and Wu Z: Protective effects of icariin on cisplatin-induced acute renal injury in mice. Am J Transl Res. 7:2105–2114. 2015.PubMed/NCBI
12	Huang Z, He L, Huang D, Lei S and Gao J: Icariin protects rats against 5/6 nephrectomy-induced chronic kidney failure by increasing the number of renal stem cells. BMC Complement Altern Med. 15:3782015. View Article : Google Scholar : PubMed/NCBI
13	Li YC, Ding XS, Li HM and Zhang C: Icariin attenuates high glucose-induced type IV collagen and fibronectin accumulation in glomerular mesangial cells by inhibiting transforming growth factor-β production and signalling through G protein-coupled oestrogen receptor 1. Clin Exp Pharmacol Physiol. 40:635–643. 2013. View Article : Google Scholar : PubMed/NCBI
14	National Research Council (US) Committee for the Update of the Guide for the C and Use of Laboratory Animals: Guide for the Care and Use of Laboratory Animals. 8th. National Academies Press (US); Washington (DC): 2011
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Lin CL, Lee PH, Hsu YC, Lei CC, Ko JY, Chuang PC, Huang YT, Wang SY, Wu SL and Chen YS: MicroRNA-29a promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction. J Am Soc Nephrol. 25:1698–1709. 2014. View Article : Google Scholar : PubMed/NCBI
17	Garovic VD, Wagner SJ, Petrovic LM, Gray CE, Hall P, Sugimoto H, Kalluri R and Grande JP: Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia. Nephrol Dial Transplant. 22:1136–1143. 2007. View Article : Google Scholar : PubMed/NCBI
18	Hering L, Herse F, Geusens N, Verlohren S, Wenzel K, Staff AC, Brosnihan KB, Huppertz B, Luft FC and Muller DN: Effects of circulating and local uteroplacental angiotensin II in rat pregnancy. Hypertension. 56:311–318. 2010. View Article : Google Scholar : PubMed/NCBI
19	Shah DM: Role of the renin-angiotensin system in the pathogenesis of preeclampsia. Am J Physiol Renal Physiol. 288:F614–625. 2005. View Article : Google Scholar : PubMed/NCBI
20	Huang JH, Cai WJ, Zhang XM and Shen ZY: Icariin promotes self-renewal of neural stem cells: An involvement of extracellular regulated kinase signaling pathway. Chin J Integr Med. 20:107–115. 2014. View Article : Google Scholar : PubMed/NCBI
21	Takahashi A, Fukusumi Y, Yamazaki M, Kayaba M, Kitazawa Y, Tomita M and Kawachi H: Angiotensin II type 1 receptor blockade ameliorates proteinuria in puromycin aminonucleoside nephropathy by inhibiting the reduction of NEPH1 and nephrin. J Nephrol. 27:627–634. 2014. View Article : Google Scholar : PubMed/NCBI
22	Forbes JM, Bonnet F, Russo LM, Burns WC, Cao Z, Candido R, Kawachi H, Allen TJ, Cooper ME, Jerums G and Osicka TM: Modulation of nephrin in the diabetic kidney: Association with systemic hypertension and increasing albuminuria. J Hypertens. 20:985–992. 2002. View Article : Google Scholar : PubMed/NCBI
23	Putaala H, Soininen R, Kilpeläinen P, Wartiovaara J and Tryggvason K: The murine nephrin gene is specifically expressed in kidney, brain and pancreas: Inactivation of the gene leads to massive proteinuria and neonatal death. Hum Mol Genet. 10:1–8. 2001. View Article : Google Scholar : PubMed/NCBI
24	Wada Y, Abe M, Moritani H, Mitori H, Kondo M, Tanaka-Amino K, Eguchi M, Imasato A, Inoki Y and Kajiyama H: Original research: Potential of urinary nephrin as a biomarker reflecting podocyte dysfunction in various kidney disease models. Exp Biol Med (Maywood). 241:1865–1876. 2016. View Article : Google Scholar : PubMed/NCBI
25	Solomon SD, Janardhanan R, Verma A, Bourgoun M, Daley WL, Purkayastha D, Lacourcière Y, Hippler SE, Fields H and Naqvi TZ: Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: A randomised trial. Lancet. 369:2079–2087. 2007. View Article : Google Scholar : PubMed/NCBI
26	Seki H: The role of the renin-angiotensin system in the pathogenesis of preeclampsia - new insights into the renin-angiotensin system in preeclampsia. Med Hypotheses. 82:362–367. 2014. View Article : Google Scholar : PubMed/NCBI
27	Weir RJ, Paintin DB, Brown JJ, Fraser R, Lever AF, Robertson JI and Young J: A serial study in pregnancy of the plasma concentrations of renin, corticosteroids, electrolytes and proteins and of haematocrit and plasma volume. J Obstet Gynaecol Br Commonw. 78:590–602. 1971. View Article : Google Scholar : PubMed/NCBI
28	Irani RA and Xia Y: Renin angiotensin signaling in normal pregnancy and preeclampsia. Semin Nephrol. 31:47–58. 2011. View Article : Google Scholar : PubMed/NCBI
29	Shirasuna K, Karasawa T, Usui F, Kobayashi M, Komada T, Kimura H, Kawashima A, Ohkuchi A, Taniguchi S and Takahashi M: NLRP3 deficiency improves angiotensin II-induced hypertension but not fetal growth restriction during pregnancy. Endocrinology. 156:4281–4292. 2015. View Article : Google Scholar : PubMed/NCBI