Diphenyl diselenide protects against diabetic kidney disease through modulating gut microbiota dysbiosis in streptozotocin-induced diabetic rats

Xing Wang; Dongmei Long; Xingcan Peng; Jiaxuan Li; Maoting Zhou; Yu Wang; Xianghong Hu

doi:10.3389/fphar.2024.1506398

Diphenyl diselenide protects against diabetic kidney disease through modulating gut microbiota dysbiosis in streptozotocin-induced diabetic rats

Front Pharmacol. 2024 Dec 3:15:1506398. doi: 10.3389/fphar.2024.1506398. eCollection 2024.

Authors

Xing Wang¹, Dongmei Long², Xingcan Peng¹, Jiaxuan Li¹, Maoting Zhou¹, Yu Wang¹, Xianghong Hu¹

Affiliations

¹ Department of Pharmacology, School of Pharmacy, North Sichuan Medical College, Nanchong, China.
² Nanchong Key Laboratory of Disease Prevention, Control and Detection in Livestock and Poultry, Nanchong Vocational and Technical College, Nanchong, China.

Abstract

Introduction: Diphenyl diselenide (DPDS) ameliorates nephropathy in streptozotocin (STZ)-induced type 1 diabetic rats by inhibiting oxidative stress and inflammatory reactions. However, it has not been clarified whether DPDS alleviates type 1 diabetic kidney disease (DKD) is related to the inhibition of extracellular matrix (ECM) production and the regulation of intestinal flora disorder.

Methods: The present study investigated the effects of DPDS on ECM generation in the kidney and intestinal microflora composition in feces. The rats were orally administered DPDS or metformin for eight weeks. Various indices were measured to assess the severity of renal injury. After euthanizing the rats, oxidative stress markers in serum and kidney were assessed using biochemical methods, and the expressions of ECM-related proteins in kidney were analyzed using Western blot. Additionally, 16S rRNA high-throughput sequencing was used to evaluate the diversity and composition of the intestinal flora in feces.

Results: The results showed DPDS and metformin improved the DKD in STZ rats, as evidenced by decreased blood glucose, BUN, urine volume, urine microalbumin, urinary β2 microglobulin, and improvement of renal pathological morphology. Furthermore, DPDS intervention markedly reduced the protein expression of α-SMA, COI Ⅳ, FN, and vimentin in the kidneys. Besides, DPDS not only improved dyslipidemia in STZ diabetic rats, but also enhanced the activities of antioxidant enzymes, decreased the level of MDA in serum and kidney, and regulated the expression of proteins related to the Nrf2/Keap1 signaling pathway in the kidney. Moreover, we found that DPDS could selectively improve the relative abundance of probiotics as well as the diversity of flora, thus ameliorating the intestinal microbial composition of the STZ rats, significantly regulating the intestinal microbial homeostasis.

Discussion: Overall, DPDS inhibited ECM production and improved renal pathological changes, which may be related to reducing oxidative stress damage in the kidney and improving intestinal flora imbalance, providing data support for the further development and application of DPDS in DKD.

Keywords: Nrf2/Keap1 signaling; diabetic nephropathy; diphenyl diselenide; extracellular matrix; gut microbiota; oxidative stress.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The present study was supported by Youth Science Fund of Sichuan Natural Science Foundation (No. 23NSFSC1676), the Municipal-school Cooperative Scientific Research Project (No. 22SXZRKX0012), the Nanchong science and technology plan project (No. 23YYJCYJ0026), the Innovation and Entrepreneurship Training Program for College Students in Sichuan Province (Nos. 202210634012, S202310634043, S202310634066), the North Sichuan Medical College PhD Research Fund (No. CBY21-QD16), the Scientific Cultivation Project of Outstanding Young People in North Sichuan Medical College (No. CBY23-JQ03), and the Scientific research development plan project of the affiliated hospital of clinical medical college of North Sichuan Medical College (No. 2023PTZK022).