Protective effect of H<sub>2</sub>S on LPS‑induced AKI by promoting autophagy

Li,Ting; Zhao,Jie; Miao,Shuying; Chen,Yiyang; Xu,Yunfei; Liu,Ying

doi:10.3892/mmr.2022.12612

March-2022 Volume 25 Issue 3

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

March-2022 Volume 25 Issue 3

Full Size Image

Article Open Access

Protective effect of H₂S on LPS‑induced AKI by promoting autophagy

Authors:
- Ting Li
- Jie Zhao
- Shuying Miao
- Yiyang Chen
- Yunfei Xu
- Ying Liu
View Affiliations / Copyright

Affiliations: Department of Physiology, Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410078, P.R. China, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, P.R. China, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, P.R. China

Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 96
|
Published online on: January 20, 2022

https://doi.org/10.3892/mmr.2022.12612
Expand metrics +

Abstract

The present study explored the protective effect of exogenous hydrogen sulfide (H₂S) on lipopolysaccharide (LPS)‑induced acute kidney injury (AKI) and the underlying mechanisms. To establish an AKI injury mouse model, LPS (10 mg/kg) was intraperitoneally injected into mice pretreated with 0.8 mg/kg sodium hydrosulfide hydrate (NaHS), an H₂S donor. The mouse survival rate and the degree of kidney injury were examined. To construct a cell damage model, HK‑2 cells were pretreated with different concentrations (0.1, 0.3 and 0.5 mM) of NaHS, and then the cells were stimulated with LPS (1 µg/ml). The cell viability, autophagy, apoptosis levels and the release of inflammatory factors were examined in mouse kidney tissue and HK‑2 renal tubular epithelial cells. It was found that pretreatment with NaHS significantly improved the survival rate of septic AKI mice, and reduced the renal damage, release of inflammatory factors and apoptosis. In HK‑2 cells, NaHS protected cells from LPS caused damage via promoting autophagy and inhibiting apoptosis and the release of inflammatory factors. In order to clarify the relationship between autophagy and apoptosis and inflammatory factors, this study used 3‑methyladenine (3‑MA) to inhibit autophagy. The results revealed that 3‑MA eliminated the protective effect of NaHS in HK‑2 cells and AKI mice. Overall, NaHS can protect from LPS‑induced AKI by promoting autophagy and inhibiting apoptosis and the release of inflammatory factors.

View Figures

View References

1	Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulmé R, et al: Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med. 28:108–121. 2002. View Article : Google Scholar : PubMed/NCBI
2	Hotchkiss RS and Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med. 348:138–50. 2003. View Article : Google Scholar : PubMed/NCBI
3	Bagshaw SM, George C and Bellomo R; ANZICS Database Management Committee, : Early acute kidney injury and sepsis: A multicentre evaluation. Crit Care. 12:R472008. View Article : Google Scholar : PubMed/NCBI
4	Mehta RL, Bouchard J, Soroko SB, Ikizler TA, Paganini EP, Chertow GM and Himmelfarb J; Program to Improve Care in Acute Renal Disease (PICARD) Study Group, : Sepsis as a cause and consequence of acute kidney injury: Program to improve care in Acute Renal Disease. Intensive Care Med. 37:241–248. 2011. View Article : Google Scholar : PubMed/NCBI
5	Gomez H, Ince C, De Backer D, Pickkers P, Payen D, Hotchkiss J and Kellum JA: A unified theory of sepsis-induced acute kidney injury: Inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock. 41:3–11. 2014. View Article : Google Scholar : PubMed/NCBI
6	Peerapornratana S, Manrique-Caballero CL, Gómez H and Kellum JA: Acute kidney injury from sepsis: Current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int. 96:1083–1099. 2019. View Article : Google Scholar : PubMed/NCBI
7	Szabo C: Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov. 6:917–935. 2007. View Article : Google Scholar : PubMed/NCBI
8	Ahangarpour A, Abdollahzade Fard A, Gharibnaseri MK, Jalali T and Rashidi I: Hydrogen sulfide ameliorates the kidney dysfunction and damage in cisplatin-induced nephrotoxicity in rat. Vet Res Forum. 5:121–127. 2014.PubMed/NCBI
9	Bos EM, Leuvenink HG, Snijder PM, Kloosterhuis NJ, Hillebrands JL, Leemans JC, Florquin S and van Goor H: Hydrogen sulfide-induced hypometabolism prevents renal ischemia/reperfusion injury. J Am Soc Nephrol. 20:1901–1905. 2009. View Article : Google Scholar : PubMed/NCBI
10	Han SJ, Kim JI, Park JW and Park KM: Hydrogen sulfide accelerates the recovery of kidney tubules after renal ischemia/reperfusion injury. Nephrol Dial Transplant. 30:1497–1506. 2015. View Article : Google Scholar : PubMed/NCBI
11	Zhu JX, Kalbfleisch M, Yang YX, Bihari R, Lobb I, Davison M, Mok A, Cepinskas G, Lawendy AR and Sener A: Detrimental effects of prolonged warm renal ischaemia-reperfusion injury are abrogated by supplemental hydrogen sulphide: An analysis using real-time intravital microscopy and polymerase chain reaction. BJU Int. 110:E1218–E1227. 2012. View Article : Google Scholar : PubMed/NCBI
12	Zhou X, Feng Y, Zhan Z and Chen J: Hydrogen sulfide alleviates diabetic nephropathy in a streptozotocin-induced diabetic rat model. J Biol Chem. 289:28827–28834. 2014. View Article : Google Scholar : PubMed/NCBI
13	Lee HJ, Mariappan MM, Feliers D, Cavaglieri RC, Sataranatarajan K, Abboud HE, Choudhury GG and Kasinath BS: Hydrogen sulfide inhibits high glucose-induced matrix protein synthesis by activating AMP-activated protein kinase in renal epithelial cells. J Biol Chem. 287:4451–4461. 2012. View Article : Google Scholar : PubMed/NCBI
14	Safar MM and Abdelsalam RM: H2S donors attenuate diabetic nephropathy in rats: Modulation of oxidant status and polyol pathway. Pharmacol Rep. 67:17–23. 2015. View Article : Google Scholar : PubMed/NCBI
15	Jiang D, Zhang Y, Yang M, Wang S, Jiang Z and Li Z: Exogenous hydrogen sulfide prevents kidney damage following unilateral ureteral obstruction. Neurourol Urodyn. 33:538–543. 2014. View Article : Google Scholar : PubMed/NCBI
16	Song K, Wang F, Li Q, Shi YB, Zheng HF, Peng H, Shen HY, Liu CF and Hu LF: Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy. Kidney Int. 85:1318–1329. 2014. View Article : Google Scholar : PubMed/NCBI
17	Dursun M, Otunctemur A, Ozbek E, Sahin S, Besiroglu H, Ozsoy OD, Cekmen M, Somay A and Ozbay N: Protective effect of hydrogen sulfide on renal injury in the experimental unilateral ureteral obstruction. Int Braz J Urol. 41:1185–1193. 2015. View Article : Google Scholar : PubMed/NCBI
18	Chen Y, Jin S, Teng X, Hu Z, Zhang Z, Qiu X, Tian D and Wu Y: Hydrogen sulfide attenuates LPS-Induced acute kidney injury by inhibiting inflammation and oxidative stress. Oxid Med Cell Longev. 2018:67172122018. View Article : Google Scholar : PubMed/NCBI
19	Levine B and Klionsky DJ: Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev Cell. 6:463–477. 2004. View Article : Google Scholar : PubMed/NCBI
20	Mizushima N, Yoshimori T and Ohsumi Y: The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 27:107–132. 2011. View Article : Google Scholar : PubMed/NCBI
21	Hsiao HW, Tsai KL, Wang LF, Chen YH, Chiang PC, Chuang SM and Hsu C: The decline of autophagy contributes to proximal tubular dysfunction during sepsis. Shock. 37:289–296. 2012. View Article : Google Scholar : PubMed/NCBI
22	Leventhal JS, Ni J, Osmond M, Lee K, Gusella GL, Salem F and Ross MJ: Autophagy limits endotoxemic acute kidney injury and alters renal tubular epithelial cell cytokine expression. PLoS One. 11:e1500012016. View Article : Google Scholar : PubMed/NCBI
23	Jiang M, Wei Q, Dong G, Komatsu M, Su Y and Dong Z: Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 82:1271–1283. 2012. View Article : Google Scholar : PubMed/NCBI
24	Liu S, Hartleben B, Kretz O, Wiech T, Igarashi P, Mizushima N, Walz G and Huber TB: Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy. 8:826–837. 2012. View Article : Google Scholar : PubMed/NCBI
25	Li T, Liu Y, Zhao J, Miao S, Xu Y, Liu K, Liu M, Wang G and Xiao X: Aggravation of acute kidney injury by mPGES-2 down regulation is associated with autophagy inhibition and enhanced apoptosis. Sci Rep. 7:102472017. View Article : Google Scholar : PubMed/NCBI
26	Yang F, Zhang L, Gao Z, Sun X, Yu M, Dong S, Wu J, Zhao Y, Xu C, Zhang W and Lu F: Exogenous H2S protects against diabetic cardiomyopathy by activating autophagy via the AMPK/mTOR Pathway. Cell Physiol Biochem. 43:1168–1187. 2017. View Article : Google Scholar : PubMed/NCBI
27	Liu Y, Liao R, Qiang Z, Yang W, Cao J and Zeng H: Exogenous H₂S protects colon cells in ulcerative colitis by inhibiting NLRP3 and activating autophagy. DNA Cell Biol. 40:748–756. 2021. View Article : Google Scholar : PubMed/NCBI
28	Zhang S, Yang G, Guan W, Li B, Feng X and Fan H: Autophagy plays a protective role in sodium hydrosulfide-induced acute lung injury by attenuating oxidative stress and inflammation in rats. Chem Res Toxicol. 34:857–864. 2021. View Article : Google Scholar : PubMed/NCBI
29	Zhao Y, Feng X, Li B, Sha J, Wang C, Yang T, Cui H and Fan H: Dexmedetomidine protects against lipopolysaccharide-induced acute kidney injury by enhancing autophagy through inhibition of the PI3K/AKT/mTOR pathway. Front Pharmacol. 11:1282020. View Article : Google Scholar : PubMed/NCBI
30	Hu L, Guo J, Zhou L, Zhu S, Wang C, Liu J, Hu S, Yang M and Lin C: Hydrogen sulfide protects retinal pigment epithelial cells from oxidative stress-induced apoptosis and affects autophagy. Oxid Med Cell Longev. 2020:88685642020. View Article : Google Scholar : PubMed/NCBI
31	Lerolle N, Nochy D, Guérot E, Bruneval P, Fagon JY, Diehl JL and Hill G: Histopathology of septic shock induced acute kidney injury: Apoptosis and leukocytic infiltration. Intensive Care Med. 36:471–478. 2010. View Article : Google Scholar : PubMed/NCBI
32	Zhang B, Ramesh G, Uematsu S, Akira S and Reeves WB: TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. J Am Soc Nephrol. 19:923–932. 2008. View Article : Google Scholar : PubMed/NCBI
33	Ho AW, Wong CK and Lam CW: Tumor necrosis factor-alpha up-regulates the expression of CCL2 and adhesion molecules of human proximal tubular epithelial cells through MAPK signaling pathways. Immunobiology. 213:533–544. 2008. View Article : Google Scholar : PubMed/NCBI
34	Allam R, Scherbaum CR, Darisipudi MN, Mulay SR, Hägele H, Lichtnekert J, Hagemann JH, Rupanagudi KV, Ryu M, Schwarzenberger C, et al: Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J Am Soc Nephrol. 23:1375–1388. 2012. View Article : Google Scholar : PubMed/NCBI
35	Hosoki R, Matsuki N and Kimura H: The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun. 237:527–531. 1997. View Article : Google Scholar : PubMed/NCBI
36	Lin F, Liao C, Sun Y, Zhang J, Lu W, Bai Y, Liao Y, Li M, Ni X, Hou Y, et al: Hydrogen sulfide inhibits cigarette smoke-induced endoplasmic reticulum stress and apoptosis in bronchial epithelial cells. Front Pharmacol. 8:6752017. View Article : Google Scholar : PubMed/NCBI
37	Feng X, Zhang H, Shi M, Chen Y, Yang T and Fan H: Toxic effects of hydrogen sulfide donor NaHS induced liver apoptosis is regulated by complex IV subunits and reactive oxygen species generation in rats. Environ Toxicol. 35:322–332. 2020. View Article : Google Scholar : PubMed/NCBI
38	Ahmad A, Druzhyna N and Szabo C: Delayed treatment with sodium hydrosulfide improves regional blood flow and alleviates cecal ligation and puncture (CLP)-Induced septic shock. Shock. 46:183–193. 2016. View Article : Google Scholar : PubMed/NCBI
39	Chen YH, Teng X, Hu ZJ, Tain DY, Jin S and Wu YM: Hydrogen sulfide attenuated sepsis-induced myocardial dysfunction through TLR4 pathway and endoplasmic reticulum stress. Front Physiol. 12:6536012021. View Article : Google Scholar : PubMed/NCBI
40	Sun L, Zhang S, Yu C, Pan Z, Liu Y, Zhao J, Wang X, Yun F, Zhao H, Yan S, et al: Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway. Am J Physiol Endocrinol Metab. 309:E925–E935. 2015. View Article : Google Scholar : PubMed/NCBI
41	Yang C, Kaushal V, Shah SV and Kaushal GP: Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells. Am J Physiol Renal Physiol. 294:F777–F787. 2008. View Article : Google Scholar : PubMed/NCBI
42	Periyasamy-Thandavan S, Jiang M, Wei Q, Smith R, Yin XM and Dong Z: Autophagy is cytoprotective during cisplatin injury of renal proximal tubular cells. Kidney Int. 74:631–640. 2008. View Article : Google Scholar : PubMed/NCBI
43	Kaushal GP, Kaushal V, Herzog C and Yang C: Autophagy delays apoptosis in renal tubular epithelial cells in cisplatin cytotoxicity. Autophagy. 4:710–712. 2008. View Article : Google Scholar : PubMed/NCBI
44	Herzog C, Yang C, Holmes A and Kaushal GP: zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function. Am J Physiol Renal Physiol. 303:F1239–F1250. 2012. View Article : Google Scholar : PubMed/NCBI
45	Yang Z and Klionsky DJ: Mammalian autophagy: Core molecular machinery and signaling regulation. Curr Opin Cell Biol. 22:124–131. 2010. View Article : Google Scholar : PubMed/NCBI
46	Han J, Bae J, Choi CY, Choi SP, Kang HS, Jo EK, Park J, Lee YS, Moon HS, Park CG, et al: Autophagy induced by AXL receptor tyrosine kinase alleviates acute liver injury via inhibition of NLRP3 inflammasome activation in mice. Autophagy. 12:2326–2343. 2016. View Article : Google Scholar : PubMed/NCBI
47	Tong Z, Jiang B, Zhang L, Liu Y, Gao M, Jiang Y, Li Y, Lu Q, Yao Y and Xiao X: HSF-1 is involved in attenuating the release of inflammatory cytokines induced by LPS through regulating autophagy. Shock. 41:449–453. 2014. View Article : Google Scholar : PubMed/NCBI
48	Zhang GY, Lu D, Duan SF, Gao YR, Liu SY, Hong Y, Dong PZ, Chen YG, Li T, Wang DY, et al: Hydrogen sulfide alleviates lipopolysaccharide-induced diaphragm dysfunction in rats by reducing apoptosis and inflammation through ROS/MAPK and TLR4/NF-κB signaling pathways. Oxid Med Cell Longev. 2018:96478092018. View Article : Google Scholar : PubMed/NCBI
49	Han X, Mao Z, Wang S, Xin Y, Li P, Maharjan S and Zhang B: GYY4137 protects against MCAO via p38 MAPK mediated anti-apoptotic signaling pathways in rats. Brain Res Bull. 158:59–65. 2020. View Article : Google Scholar : PubMed/NCBI
50	Wang H, Zhong P and Sun L: Exogenous hydrogen sulfide mitigates NLRP3 inflammasome-mediated inflammation through promoting autophagy via the AMPK-mTOR pathway. Biol Open. 8:bio0436532019. View Article : Google Scholar : PubMed/NCBI
51	Zhao S, Song T, Gu Y, Zhang Y, Cao S, Miao Q, Zhang X, Chen H, Gao Y, Zhang L, et al: Hydrogen sulfide alleviates liver injury Through the S-Sulfhydrated-Kelch-Like ECH-Associated Protein 1/Nuclear Erythroid 2-Related Factor 2/Low-Density Lipoprotein Receptor-Related Protein 1 pathway. Hepatology. 73:282–302. 2021. View Article : Google Scholar : PubMed/NCBI
52	Wu J, Tian Z, Sun Y, Lu C, Liu N, Gao Z, Zhang L, Dong S, Yang F, Zhong X, et al: Exogenous H₂S facilitating ubiquitin aggregates clearance via autophagy attenuates type 2 diabetes-induced cardiomyopathy. Cell Death Dis. 8:e29922017. View Article : Google Scholar : PubMed/NCBI
53	Zhao S, Yang L, Li L and Fan Z: NaHS alleviated cell apoptosis and mitochondrial dysfunction in remote lung tissue after renal ischemia and reperfusion via Nrf2 activation-mediated NLRP3 pathway inhibition. Biomed Res Int. 2021:55988692021. View Article : Google Scholar : PubMed/NCBI

Journals