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Original Article

Korean J Physiol Pharmacol 2022; 26(6): 427-438

Published online November 1, 2022 https://doi.org/10.4196/kjpp.2022.26.6.427

Copyright © Korean J Physiol Pharmacol.

The role of discoid domain receptor 1 on renal tubular epithelial pyroptosis in diabetic nephropathy

Weichen Zhao, Chunyuan He, Junjie Jiang, Zongbiao Zhao, Hongzhong Yuan, Facai Wang*, and Bingxiang Shen*

Department of Pharmacy, Lu'an Hospital Affiliated to Anhui Medical University, Lu’an People’s Hospital, Lu'an, Anhui 237005, China

Correspondence to:Facai Wang
E-mail: wfclayy@163.com
Bingxiang Shen
E-mail: sbxlayy@163.com

Author contributions: W.Z., F.W., and B.S. designed the research. W.Z., C.H., J.J., Z.Z., and H.Y. participated in the experiments. W.Z. and C.H. analyzed the data. W.Z. wrote the manuscript. F.W. offered funding. All authors have read and agreed to the published version of the manuscript.

Received: January 16, 2022; Revised: April 13, 2022; Accepted: April 13, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Pyroptosis, a form of cell death associated with inflammation, is known to be involved in diabetic nephropathy (DN), and discoid domain receptor 1 (DDR1), an inflammatory regulatory protein, is reported to be associated with diabetes. However, the mechanism underlying DDR1 regulation and pyroptosis in DN remains unknown. We aimed to investigate the effect of DDR1 on renal tubular epithelial cell pyroptosis and the mechanism underlying DN. In this study, we used high glucose (HG)-treated HK-2 cells and rats with a single intraperitoneal injection of streptozotocin as DN models. Subsequently, the expression of pyroptosis-related proteins (cleaved caspase-1, GSDMD-N, Interleukin-1β [IL-1β], and interleukin-18 [IL-18]), DDR1, phosphorylated NF-κB (p-NF-κB), and NLR family pyrin domain-containing 3 (NLRP3) inflammasomes were determined through Western blotting. IL-1β and IL-18 levels were determined using ELISA. The rate of pyroptosis was assessed by propidium iodide (PI) staining. The results revealed upregulated expression of pyroptosis-related proteins and increased concentration of IL-1β and IL-18, accompanied by DDR1, p-NF-κB, and NLRP3 upregulation in DN rat kidney tissues and HG-treated HK-2 cells. Moreover, DDR1 knockdown in the background of HG treatment resulted in inhibited expression of pyroptosis-related proteins and attenuation of IL-1β and IL-18 production and PI-positive cell frequency via the NF-κB/NLRP3 pathway in HK-2 cells. However, NLRP3 overexpression reversed the effect of DDR1 knockdown on pyroptosis. In conclusion, we demonstrated that DDR1 may be associated with pyroptosis, and DDR1 knockdown inhibited HG-induced renal tubular epithelial cell pyroptosis. The NF-κB/NLRP3 pathway is probably involved in the underlying mechanism of these findings.

Keywords: Diabetic nephropathy, Discoid domain receptor 1, NLR family pyrin domain-containing 3, Nuclear factor kappa B, Pyroptosis