Sodium‐Glucose Cotransporter‐2 Inhibitor Suppresses Endoplasmic Reticulum Stress and Oxidative Stress in Diabetic Nephropathy Through Nrf2 Signaling: A Clinical and Experimental Study

Author:

Prasad Murali Krishna1,Victor Paul S.1,Ganesh Goutham V.1,Juttada Udayama2,Kumpatla Satyavani2,Viswanathan Vijay2,Ramkumar Kunka Mohanram1

Affiliation:

1. Department of Biotechnology School of Bioengineering, SRM Institute of Science and Technology Kattankulathur Tamilnadu India

2. Department of Biochemistry and Molecular Genetics Prof. M. Viswanathan's Diabetes Research Center M.V. Hospital for Diabetes Royapuram Chennai Tamilnadu India

Abstract

AbstractDiabetic nephropathy (DN), a severe complication of type 2 diabetes mellitus (T2DM), is marked by heightened endoplasmic reticulum stress (ERS) and oxidative stress (OS) due to protein misfolding and free radical generation. We investigated the sodium‐glucose co‐transporter‐2 inhibitor (SGLT2i), canagliflozin (Cana), in alleviating ERS and OS in DN patients and THP‐1 cells under hyperglycemic condition. A total of 120 subjects were divided into four groups, with 30 subjects in each group: healthy controls, T2DM individuals, DN patients receiving standard treatment, and those treated with Cana. The control group had no history of diabetes, cardiovascular or renal diseases, or other comorbidities. Cana was administered at doses of either 100 or 300 mg per day based on the estimated glomerular filtration rate (eGFR) value of DN individuals, with a mean follow‐up of 6 months. Additionally, THP‐1 monocytes were exposed to HGM (33.3 mM glucose with a cytokine cocktail of TNF‐α and IFN‐γ at 50 ng/mL each) to evaluate the relative levels of ERS, OS markers, and nuclear factor erythroid 2‐related factor 2 (Nrf2), the transcription factor regulating cellular redox, which is downregulated in diabetes. Our results revealed that ERS markers GRP78 and PERK, as well as OS markers TXNIP and p22phox, were elevated in both DN patients and HGM‐treated THP‐1 monocytes and were reduced by Cana intervention. Furthermore, Cana regulated the phosphorylation of Nrf2, Akt, and EIF2α in HGM‐treated monocytes. In conclusion, our findings highlight the role of Cana in activating Nrf2, thereby attenuating ERS and OS to mitigate DN progression.

Funder

SRM Institute of Science and Technology

Publisher

Wiley

Reference39 articles.

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