Division of Nephrology, Department of Medicine, Dorrance Hamilton Research Labs, Thomas Jefferson University, Philadelphia, PA, 19107

Correspondence: Kumar Sharma, M.D., Thomas Jefferson University, 1020 Locust Street, Suite 353, Jefferson Alumni Hall, Philadelphia, Pennsylvania, 19107, USA. E-mail: kumar.sharma@mail.tju.edu

Abstract

Regulation of inositol 1,4,5-trisphosphate receptors by transforming growth factor-: Implications for vascular dysfunction in diabetes. Diabetes in its early stages is associated with enhanced glomerular blood flow and systemic vasodilation. Possible consequences of enhanced glomerular blood flow are glomerular hypertrophy, increased shear stress, and subsequent glomerulosclerosis. The prosclerotic cytokine, transforming growth factor-beta (TGF-), has been well established to play a key role in mesangial matrix accumulation in diabetes; however, its role in regulating vascular tone has not been studied in depth. Earlier studies have demonstrated that vascular smooth muscle cells and mesangial cells pretreated with TGF- have impaired calcium mobilization to inositol 1,4,5-trisphosphate (IP₃) generating agonists, such as platelet-derived growth factor (PDGF) and Angiotensin II (Ang II). We postulated that this action of TGF- may be caused by regulation of the key intracellular calcium channel, the inositol 1,4,5-trisphosphate receptor (IP₃R). Mesangial and smooth muscle cells primarily contain the types I IP₃R and III IP₃R isoforms. Short-term exposure of mesangial cells to TGF- (15–60 min) leads to phosphorylation of the type I IP₃R at specific serine residues. Long-term exposure of mesangial cells to TGF- (24 hours) leads to down-regulation of protein levels of both types I and III IP₃Rs as assessed by Western blot and confocal analysis. Permeabilization of cells and exposure to IP₃ leads to impaired calcium mobilization if cells are pretreated with TGF-. As an in vivo correlation, we found that streptozotocin-induced diabetic rats and mice have reduced renal type I IP₃R expression. By immunostaining, we found reduction of type I IP₃R in glomerular cells and arteriolar smooth muscle cells of the diabetic rat kidney. Treatment of diabetic mice with a neutralizing anti-TGF- antibody completely prevents diabetic glomerular hypertrophy. We conclude that the vascular dysfunction of diabetes leading to glomerular hypertrophy is mediated, in part, by TGF--induced regulation of IP₃Rs.