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Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator
1Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Abstract:
Renal cells are a rich source of transforming growth factor (TGF)-beta, and they serve as targets for its actions. Our hypothesis that activation of the TGF-beta system in the kidney is implicated in the development of diabetic renal disease stems from the close similarity of actions of TGF-beta and high ambient glucose on renal cell growth and extracellular matrix metabolism. Proximal tubule cells and glomerular mesangial cells cultured in high glucose concentration express increased TGF-beta 1 mRNA and protein levels, and treatment with anti-TGF-beta antibodies results in prevention of the effects of high glucose to induce cellular hypertrophy and stimulate collagen biosynthesis. Several in vivo studies by different groups of investigators have reported overexpression of TGF-beta in the glomeruli in human and experimental diabetes. We have also observed that the development of renal hypertrophy in the insulin-dependent diabetic BB rat and NOD mouse is associated with increased expression of TGF-beta 1 in the kidney and that short-term administration of antibodies capable of neutralizing the activity of TGF-beta in the streptozotocin mouse model of diabetes results in attenuation of whole kidney and glomerular hypertrophy and overexpression of mRNAs encoding matrix components. Together, these findings are consistent with the hypothesis that the diabetic state stimulates TGF-beta expression in the kidney and that in turn this growth factor may mediate, in an autocrine/paracrine manner, some of the principal early manifestations of diabetic renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Transforming growth factor-beta (TGF-β) activation in the kidney contributes to diabetic renal disease. Neutralizing TGF-β reduces high glucose-induced kidney cell growth and matrix production.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Renal cells are targets and sources of transforming growth factor-beta (TGF-β).
- High glucose and TGF-β share similar effects on renal cell growth and extracellular matrix metabolism.
- Diabetic renal disease is characterized by kidney hypertrophy and extracellular matrix accumulation.
Purpose of the Study:
- To investigate the role of the TGF-β system in the kidney in the development of diabetic renal disease.
- To determine if TGF-β mediates the effects of high glucose on renal cells.
Main Methods:
- In vitro studies using proximal tubule and glomerular mesangial cells cultured in high glucose.
- In vivo studies in diabetic rat and mouse models (BB rat, NOD mouse, streptozotocin-induced diabetes).
- Measurement of TGF-β 1 mRNA and protein levels.
- Administration of anti-TGF-β antibodies.
Main Results:
- High glucose increased TGF-β 1 mRNA and protein in cultured renal cells.
- Anti-TGF-β antibodies prevented high glucose-induced cellular hypertrophy and collagen synthesis.
- Diabetic animal models showed increased kidney TGF-β 1 expression.
- Antibody neutralization of TGF-β attenuated kidney and glomerular hypertrophy and matrix gene expression in diabetic mice.
Conclusions:
- The diabetic state stimulates renal TGF-β expression.
- TGF-β likely mediates early manifestations of diabetic renal disease through autocrine/paracrine mechanisms.
- Targeting the TGF-β system may offer therapeutic strategies for diabetic nephropathy.