Canagliflozin ameliorates renal oxidative stress and inflammation by stimulating AMPK\u2013Akt\u2013eNOS pathway in the isoprenaline-induced oxidative stress model

Raquibul Hasan,Ferdous Khan,Faisal Parvez,Mushfera Zamila,Nusrat Subhan,Md Mizanur Rahman,Farzana Zerin,Shoumen Lasker,Md Ashraful Alam,Ahasanul Hasan

doi:10.1038/s41598-020-71599-2

Abstract

Diabetes is a leading cause of chronic kidney disease, and the high prevalence of sympathetic nervous system (SNS) hyperactivity in diabetic patients makes them further susceptible to SNS-mediated oxidative stress and accelerated kidney damage. Here, we investigated if canagliflozin can reverse isoprenaline (ISO)-induced renal oxidative damage in rats, a model that mimics SNS overstimulation-induced organ injuries in humans. We found that ISO administration elevates renal oxidative stress markers including malondialdehyde (MDA), advanced protein oxidation product (APOP), myeloperoxidase (MPO) and nitric oxide (NO), while depleting levels of endogenous antioxidants such as catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH). Strikingly, canagliflozin treatment of ISO-treated rats not only prevents elevation of oxidative stress markers but also rescues levels of depleted antioxidants. Our results also show that canagliflozin stimulates antioxidant/anti-inflammatory signaling pathways involving AMP-activated protein kinase (AMPK), Akt and eNOS, and inhibits iNOS and NADPH oxidase isoform 4 (NOX4), all of which are associated with oxidative stress and inflammation. Further, canagliflozin prevents ISO-induced apoptosis of kidney cells by inhibiting Bax protein upregulation and caspase-3 activation. Histological examination of kidney sections reveal that canagliflozin attenuates ISO-mediated increases in inflammatory cell infiltration, collagen deposition and fibrosis. Finally, consistent with these findings, canagliflozin treatment improves kidney function in ISO-treated rats, suggesting that the antioxidant effects may be clinically translatable.

Highlights

Diabetic kidney disease is a major risk factor for the development of chronic kidney disease affecting approximately 40% of global diabetic population[1]
For the first time, that canagliflozin treatment protects against kidney damage in an ISOinduced oxidative stress rat model that mimics the pathological features of oxidative kidney injury in humans, which arise due to excessive sympathetic nervous system (SNS) activity often seen in d iabetes[18,20]
We found that canagliflozin treatment augmented endogenous antioxidant defense and reduced oxidative stress markers, inflammation, fibrosis and apoptosis

Summary

Introduction

Diabetic kidney disease is a major risk factor for the development of chronic kidney disease affecting approximately 40% of global diabetic population[1]. The promising protective effects of canagliflozin against cardiac and renal oxidative stress as well as inflammation, led us to hypothesize that canagliflozin may have a broad range of antioxidant and anti-inflammatory properties against oxidative kidney damage, including that caused by SNS hyperactivity. Our data demonstrates that canagliflozin improves kidney function markers in ISO-treated rats by stimulating multiple antioxidant, anti-inflammatory and anti-apoptotic signaling pathways involving AMPK, Akt and eNOS. Together, these effects prevent ISO-induced oxidative stress caused by iNOS, NOX4, Bax and caspase-3 activation. For the first time, uncovers a novel mechanism for canagliflozin in reducing oxidative kidney damage, and raises the possibility of potential benefits of canagliflozin treatment in SNS hyperactivity-associated kidney injury in diabetes

Methods

Results

Conclusion