TY - JOUR
T1 - Regulation of inositol 1,4,5-trisphosphate receptors by transforming growth factor-β
T2 - Implications for vascular dysfunction in diabetes
AU - McGowan, T. A.
AU - Sharma, K.
N1 - Funding Information:
This work was supported by National Institutes of Health DK02308 and American Diabetes Association Research Award (KS), and National Kidney Foundation and Alyce Specter Grant (TAM). The work was performed in the Dorrance H. Hamilton Laboratories of Thomas Jefferson University.
PY - 2000
Y1 - 2000
N2 - 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-β), 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-β 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-β 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-β (15-60 min) leads to phosphorylation of the type I IP3R at specific serine residues. Long-term exposure of mesangial cells to TGF-β (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-β. 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-β antibody completely prevents diabetic glomerular hypertrophy. We conclude that the vascular dysfunction of diabetes leading to glomerular hypertrophy is mediated, in part, by TGF-β-induced regulation of IP3Rs.
AB - 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-β), 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-β 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-β 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-β (15-60 min) leads to phosphorylation of the type I IP3R at specific serine residues. Long-term exposure of mesangial cells to TGF-β (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-β. 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-β antibody completely prevents diabetic glomerular hypertrophy. We conclude that the vascular dysfunction of diabetes leading to glomerular hypertrophy is mediated, in part, by TGF-β-induced regulation of IP3Rs.
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U2 - 10.1046/j.1523-1755.2000.07716.x
DO - 10.1046/j.1523-1755.2000.07716.x
M3 - Review article
C2 - 10997698
AN - SCOPUS:0033860833
SN - 0098-6577
VL - 58
SP - S99-S103
JO - Kidney International, Supplement
JF - Kidney International, Supplement
IS - 77
ER -