Abstract P025: Hyperinsulinemia Causes Renal Hyperperfusion And Increases Glomerular Basement Membrane Thickness Independent Of Renal Perfusion Pressure And Glycemic Status: Potential Role Of Connecting Tubule Glomerular Feedback?
Obesity is often associated with hyperinsulinemia (HI) and renal damage. However, the role of HI in Obesity related Renal Damage (ORD) is unclear. Renal hyperperfusion/hyperfiltration plays a major role in ORD. Normally, the kidneys autoregulate blood flow by two feedback mechanisms: 1.) Tubuloglomerular feedback (TGF), a vasoconstrictor mechanism and 2.) Connecting Tubule Glomerular Feedback (CTGF), a vasodilator mechanism. Previously, we found that Zucker obese rats had higher CTGF (TGF was unchanged) and were hyperinsulinemic before the development of ORD. Epithelial sodium channel (ENaC) initiates CTGF and Insulin is a known ENaC activator. Hypothesis: HI increases renal cortical blood flow (CBF) by increasing CTGF and causes renal damage. To isolate the effect of HI from the blood glucose (BG) level, HI-euglycemic clamp was created in normal anesthetized Sprague Dawley (SD) rats by simultaneous intravenous (IV) infusion of 10% glucose and insulin. Average baseline BG in non-fasted anesthetized SD rats was 199.0±31.6 mmol/L. Insulin infusion increased CBF significantly by 12.2 ± 1.3% (n=3, p<0.05) from the baseline even before the BG level starts decreasing. Insulin was further infused to attain normoglycemic condition (96.0±2.3 mmol/L) and this was associated with additional increase in CBF by 19.2 ± 4.5% (p<0.05) from the baseline. Subsequent ENaC inhibition by benzamil (BZ) (400 μg/kg, IV) completely reversed the insulin-induced increase in CBF. Neither Insulin nor BZ treatment altered the renal perfusion pressure (RPP) suggesting insulin-induced increase in CBF was independent of RPP. In a separate group of SD rats, renal-HI (1.8 IU/kg/day) was created in only one of the two kidneys for 6 weeks using renal subcapsular catheter to measure glomerular basement membrane (GBM) thickness (a marker of renal damage). GBM was significantly thickened in insulin-infused kidney compared to vehicle-infused kidney (199.4±17 vs. 145.5±3.6nm, n=3, p<0.05). Conclusion: Acute HI increased CBF, that was completely reversed by ENaC inhibition implying a possible role of enhanced CTGF. Chronic renal-HI caused GBM thickening. Perspective: HI observed in obesity or type-2 diabetes may cause renal hyperperfusion by increasing CTGF and contribute to the ORD.