Inhibition of sodium-glucose cotransporter 2 ameliorates renal injury in a novel medaka model of nonalcoholic steatohepatitis-related kidney disease.

Takuro Nagoya,Kenya Kamimura,Ryo Goto,Shuji Terai,Masayoshi Ko,Atsushi Kimura,Hiroshi Nishina,Yoko Shinagawa‐Kobayashi,Yusuke Niwa,Norihiro Sakai

doi:10.1002/2211-5463.12734

Abstract

The effect of sodium‐glucose cotransporter 2 inhibitor (SGLT2I) on nonalcoholic steatohepatitis (NASH) has been reported, but there are few studies on its effect on NASH‐related renal injury. In this study, we examined the effect of SGLT2I using a novel medaka fish model of NASH‐related kidney disease, which was developed by feeding the d‐rR/Tokyo strain a high‐fat diet. SGLT2I was administered by dissolving it in water of the feeding tank. SGLT2I ameliorates macrophage accumulation and oxidative stress and maintained mitochondrial function in the kidney. The results demonstrate the effect of SGLT2I on NASH‐related renal injury and the usefulness of this novel animal model for research into NASH‐related complications.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity, diabetes, hyperlipidemia, hypertension, and insulin resistance [1,2,3] and frequently complicated with various metabolic diseases including chronic kidney disease and cardiovascular disease which can adversely impact prognosis
Disease progression is related to obesity, diabetes, hyperlipidemia, hypertension, and insulin resistance [1,2,3], and chronic renal injury and cardiovascular disease are common complications that aggravate each other and are associated with bad prognosis in patients with NAFLD/nonalcoholic steatohepatitis (NASH) [34]
We have examined the renal inflammation, oxidative stress, and mitochondrial function in a medaka model of high-fat diet (HFD)-induced renal injury that recapitulates changes in NASH-associated renal injury [26], because of the ease of maintenance of these animals under the same concentrations of chemical compounds dissolved in water and their high fecundity

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity, diabetes, hyperlipidemia, hypertension, and insulin resistance [1,2,3] and frequently complicated with various metabolic diseases including chronic kidney disease and cardiovascular disease which can adversely impact prognosis. We recently showed the preventive effect of tofogliflozin (Tofo), a highly specific SGLT2I [13], on fatty infiltration and fibrotic changes in the liver of high-fat diet (HFD)-fed medaka fish (Oryzias latipes) nonalcoholic steatohepatitis (NASH) model [25]. This model provided ease of maintenance of animals under the same condition (the same concentrations of the chemical compound dissolved in water) and high fecundity. These results demonstrate the beneficial effect of an SGLT2I in NASH-related renal injury and further reveal the utility of the medaka model of NASH in examining these effects and evaluation of other potential therapeutic compounds for NASH-related complications

Methods

Results

Conclusion