The paper is titled “Proximal tubular epithelial insulin receptor mediates high fat diet-induced kidney injury” by Hak Joo Lee, Meenalakshmi M. Mariappan, Luke Norton, Terry Bakewell, Denis Feliers, Sae Byeol Oh, Andrew Donati, Cherubina S. Rubannelsonkumar, Manjeri A. Venkatachalam, Stephen E. Harris, Isabelle Rubera, Michel Tauc, Goutam Ghosh Choudhury, C. Ronald Kahn, Kumar Sharma, Ralph A. DeFronzo, and Balakuntalam S. Kasinath. Dr. Kasinath is a Professor Emeritus in the Department of Medicine, Division of Nephrology. This paper is the culmination of his VA funded Merit Review Grant addressing the role of insulin receptor in obesity-induced kidney injury.
The role of insulin receptor (IR) activated by hyperinsulinemia in obesity-induced kidney injury is not well understood. We hypothesized that activation of the 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 knock out (KPTIRKO) mice for 4 months. Renal cortical IR expression was decreased by 60% in male and female KPTIRKO mice. In KPTIRKO mice baseline serum glucose, serum creatinine, and urinary albumin to creatinine ratio (ACR) were similar to 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 and kidney injury molecule-1 (KIM-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.