Renal type I inositol 1,4,5-trisphosphate receptor is reduced in streptozotocin-induced diabetic rats and mice

The mechanisms underlying glomerular hypertrophy and hyperfiltration in diabetes remain unclear. We have previously demonstrated that the cytokine transforming growth factor-β1 (TGF-β1) is increased in early diabetic kidney disease and TGF-β1 inhibits the expression of the inositol 1,4,5- trisphosphate (IP₃)-gated calcium channel, the type I IP₃ receptor (IP₃R), in mesangial cells. To test the hypothesis that reduced type I IP₃R may be important in diabetic kidney disease, we evaluated type I IP₃R expression in the kidney of streptozotocin-induced diabetic rats and mice. Two-week-old diabetic rats have decreased renal type I IP₃R protein and mRNA levels. Immunostaining of normal rat kidney demonstrated presence of type I IP₃R in glomerular and vascular smooth muscle cells, whereas diabetic rats had reduced staining in both compartments. Reduction of type I IP₃R also occurred in parallel with renal hypertrophy, increased creatinine clearance, and increased renal TGF-β1 expression in the diabetic rats. Two-week-old diabetic mice also had reduced renal type I IP₃R protein and mRNA expression in association with renal hypertrophy and increased TGF-β1 mRNA expression. These findings demonstrate that there is reduced type I IP₃R in glomerular and vascular smooth muscle cells in the diabetic kidney, which may contribute to the altered renal vasoregulation and renal hypertrophy of diabetes.