Regulation of inositol 1,4,5-trisphosphate receptors by transforming growth factor-β

Implications for vascular dysfunction in diabetes

T. A. McGowan, Kumar Sharma

Research output: Contribution to journalReview article

14 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalKidney International, Supplement
Volume58
Issue number77
StatePublished - Jan 1 2000
Externally publishedYes

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Inositol 1,4,5-Trisphosphate Receptors
Transforming Growth Factors
Transforming Growth Factor beta
Blood Vessels
Mesangial Cells
Hypertrophy
Smooth Muscle Myocytes
Calcium
Kidney
Inositol 1,4,5-Trisphosphate
Platelet-Derived Growth Factor
Prothrombin
Calcium Channels
Streptozocin
Vascular Smooth Muscle
Vasodilation
Angiotensin II
Serine
Protein Isoforms
Down-Regulation

ASJC Scopus subject areas

  • Nephrology

Cite this

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title = "Regulation of inositol 1,4,5-trisphosphate receptors by transforming growth factor-β: Implications for vascular dysfunction in diabetes",
abstract = "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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AU - McGowan, T. A.

AU - Sharma, Kumar

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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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VL - 58

JO - Kidney International, Supplement

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