Abstract: SA-PO504
Hyperinsulinemia Contributes to High Fat-Induced Kidney Injury in Mice
Session Information
- Diabetic Kidney Disease: Basic - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Lee, Hak Joo, University of Texas Health San Antonio, San Antonio, Texas, United States
- Mariappan, Meenalakshmi M., University of Texas Health San Antonio, San Antonio, Texas, United States
- Bakewell, Terry, University of Texas Health San Antonio, San Antonio, Texas, United States
- Norton, Luke, University of Texas Health San Antonio, San Antonio, Texas, United States
- Feliers, Denis, University of Texas Health San Antonio, San Antonio, Texas, United States
- Oh, Sae Byeol, University of Texas Health San Antonio, San Antonio, Texas, United States
- Donati, Andrew, University of Texas Health San Antonio, San Antonio, Texas, United States
- Rubannelsonkumar, Cherubina Sibyl, University of Texas Health San Antonio, San Antonio, Texas, United States
- Rubera, Isabelle, Université Côte d'Azur, CNRS, LP2M UMR7370, Nice, France
- Tauc, Michel, Université Côte d'Azur, CNRS, LP2M UMR7370, Nice, France
- Harris, Stephen E., University of Texas Health San Antonio, San Antonio, Texas, United States
- Ghosh-Choudhury, Goutam, University of Texas Health San Antonio, San Antonio, Texas, United States
- Venkatachalam, Manjeri A., University of Texas Health San Antonio, San Antonio, Texas, United States
- Sharma, Kumar, University of Texas Health San Antonio, San Antonio, Texas, United States
- DeFronzo, Ralph A., University of Texas Health San Antonio, San Antonio, Texas, United States
- Kasinath, Balakuntalam S., University of Texas Health San Antonio, San Antonio, Texas, United States
Background
The mechanism of obesity-induced kidney injury is not well understood. We hypothesized that hyperinsulinemia activates kidney proximal tubular epithelial insulin receptor (IR) and contributes to obesity-induced kidney injury in high fat diet fed mice.
Methods
We generated kidney proximal tubule IR knock out (KPTIRKO) mice by crossing IR lox mice with Sglt2-Cre mice. We administered normal fat diet (NFD) or high fat diet (HFD) to 5-8 month old male Control and KPTIRKO mice for 4 months (n=9-10/group, 2 batches) and evaluated changes in albuminuria, blood pressure (BP), renal matrix proteins, signaling pathways and intraperitoneal GTT.
Results
KPTIRKO mice grew normally. In KPTIRKO mice renal cortical IR expression was decreased by more than 60% although it was unchanged in other tissues. Serum insulin, creatinine, urinary albumin to creatinine ratio (ACR) and renal cortical IGF-1 receptor expression in KPTIRKO mice were similar to Controls. On HFD, food consumption, increase in body weight and serum cholesterol were similar in Control and KPTIRKO mice. HFD increased the following in Control mice: renal cortical content of tyrosine phosphorylated IR indicating IR activation, matrix proteins laminin, fibronectin and collagen I, urinary and renal cortical KIM-1 content, urinary ACR, systolic BP; these changes were significantly ameliorated in HFD-fed KPTIRKO mice (p<0.05-0.001). HFD activated renal cortical IR-Akt axis in Control but not KPTIRKO mice. HFD increased serum insulin and C-peptide levels in Control but not in KPTIRKO mice. To explore if improved glucose tolerance was the reason for lack of hyperinsulinemia in KPTIRKO mice on HFD, GTT was done. KPTIRKO mice on NFD had lower fasting glucose and improved glucose tolerance; however, glucose intolerance was similar in Controls and KPTIRKO mice on HFD.
Conclusion
HFD-induced hyperinsulinemia activates renal cortical IR and contributes to kidney injury manifesting as albuminuria, elevated BP, and matrix protein accumulation in male mice. These results provide a mechanistic explanation for obesity-induced kidney injury. The reason for lack of hyperinsulinemia in HFD fed KTPTIRKO mice needs further investigation.
Funding
- Veterans Affairs Support