Proximal tubular epithelial insulin receptor mediates high-fat diet-induced kidney injury.

Hak Joo Lee,Stephen E Harris,Luke Norton,Cherubina S Rubannelsonkumar,Ralph A Defronzo,Balakuntalam S Kasinath,Sae Byeol Oh,Terry Bakewell,Michel Tauc,Kumar Sharma,Meenalakshmi M Mariappan,Goutam Ghosh Choudhury,Manjeri A Venkatachalam,Andrew Donati,C Ronald Kahn,Denis Feliers,Isabelle Rubera

doi:10.1172/jci.insight.143619

Abstract

The role of insulin receptor (IR) activated by hyperinsulinemia in obesity-induced kidney injury is not well understood. We hypothesized that activation of kidney proximal tubule epithelial IR contributes to obesity-induced kidney injury. We administered normal-fat diet (NFD) or high-fat diet (HFD) to control and kidney proximal tubule IR–knockout (KPTIRKO) mice for 4 months. Renal cortical IR expression was decreased by 60% in male and female KPTIRKO mice. Baseline serum glucose, serum creatinine, and the ratio of urinary albumin to creatinine (ACR) were similar in KPTIRKO mice compared to those of controls. On HFD, weight gain and increase in serum cholesterol were similar in control and KPTIRKO mice; blood glucose did not change. HFD increased the following parameters in the male control mice: renal cortical contents of phosphorylated IR and Akt, matrix proteins, urinary ACR, urinary kidney injury molecule-1–to-creatinine ratio, and systolic blood pressure. Renal cortical generation of hydrogen sulfide was reduced in HFD-fed male control mice. All of these parameters were ameliorated in male KPTIRKO mice. Interestingly, female mice were resistant to HFD-induced kidney injury in both genotypes. We conclude that HFD-induced kidney injury requires renal proximal tubule IR activation in male mice.

Highlights

Insulin-resistant states, such as obesity, diabetes, and hypertension, are common causes of chronic kidney disease (CKD, refs. 1–3)
There was no change in the IGF-I receptor (IGF-insulin receptor (IR)) expression in the kidney cortexes of male and female kidney proximal tubule IR–knockout (KPTIRKO) mice (Supplemental Figure 3), indicating that there was no compensatory increase in IGF-IR expression for the loss of IRβ
Our data demonstrate that proximal tubular epithelial cell IR activation by hyperinsulinemia in high-fat diet (HFD)-fed mice is required for the development of albuminuria, hypertension, matrix protein accumulation, renal hypertrophy, dyslipidemia, and stimulation of signaling pathways involved in protein synthesis

Summary

Introduction

Insulin-resistant states, such as obesity, diabetes, and hypertension, are common causes of chronic kidney disease (CKD, refs. 1–3). Insulin-resistant states, such as obesity, diabetes, and hypertension, are common causes of chronic kidney disease Data from the CDC indicate that the prevalence of obesity in the US adult population is 39.8%, affecting nearly 93 million people, whereas it is 18.5% in youth [4]. Subjects with obesity carry a 2.8fold and 6.3-fold higher risk for CKD and proteinuria, respectively, after adjusting for creatinine, uric acid, hypertension, HDL-cholesterol, and hyperglycemia [7]. Studies on mechanisms through which obesity affects the kidney have assigned a role for dyslipidemia, adiponectin, angiotensin II, oxidative stress, hyperfiltration, immune activation, and lipotoxicity [8,9,10,11,12,13,14]. Whether hyperinsulinemia, a key feature in obesity, plays a pathogenic role has not been directly examined

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