The DR1‑CSE/H<sub>2</sub>S system inhibits renal fibrosis by downregulating the ERK1/2 signaling pathway in diabetic mice

Li,Hongzhu; Sun,Fengqi; Bai,Shuzhi; Chang,Guiquan; Wu,Ren; Wei,Yaxin; Wen,Xin; Xi,Yuxin; Hao,Jinghui; Zaid,Altaany

doi:10.3892/ijmm.2021.5062

The DR1‑CSE/H₂S system inhibits renal fibrosis by downregulating the ERK1/2 signaling pathway in diabetic mice

Authors:
- Hongzhu Li
- Fengqi Sun
- Shuzhi Bai
- Guiquan Chang
- Ren Wu
- Yaxin Wei
- Xin Wen
- Yuxin Xi
- Jinghui Hao
- Altaany Zaid
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Affiliations: Department of Pathophysiology, School of Medicine, Xiamen University, Xiamen, Fujian 361100, P.R. China, Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
Published online on: November 11, 2021 https://doi.org/10.3892/ijmm.2021.5062
Article Number: 7
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Glomerular mesangial cell (MC) proliferation and extracellular matrix deposition are the main pathological changes in diabetic nephropathy. Hydrogen sulfide (H₂S) inhibits the proliferation of MCs. Dopamine 1 receptors (DR1) are expressed in MCs and serve important physiological roles. However, it is unclear whether DR1 activation inhibits MC proliferation by increasing endogenous H₂S. The present study found that the production of H₂S and the expression of DR1 and cystathionine‑γ‑lyase (CSE) were decreased in the renal tissues of diabetic mice and high glucose (HG)‑induced MCs. SKF38393 (a DR1 agonist) increased the production of H₂S and the expression of DR1 and CSE and NaHS (an exogenous H₂S donor) only increased H₂S production and CSE expression but not DR1 expression. HG increased the thickness of the glomerular basement membrane, cell viability and proliferation, the expression of cyclin D1, PCNA, collagen 1 and α‑smooth muscle actin and the activity of phosphorylated ERK1/2 and decreased the expression of P21 and MMP9. SKF38393 and NaHS reversed the effects of HG. PPG (a CSE inhibitor) abolished the beneficial effects of SKF38393. The beneficial effects of SKF38393 were similar to those of PD98059 (an ERK1/2 inhibitor). Taken together, the findings suggested that the DR1‑CSE/H₂S pathway activation attenuated diabetic MC proliferation and extracellular matrix deposition by downregulating the ERK1/2 signaling pathway.

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