Novel Aspects of Transforming Growth Factor-Beta in Diabetic Kidney Disease

Tsuchida, Kenichi; Cronin, Brian; Sharma, Kumar

doi:10.1159/000064486

Cited by 17 publications

(15 citation statements)

References 135 publications

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“…Elevated intraglomerular pressure has been linked to the development of mesangial cell matrix overproduction and podocyte injury with thickening of the glomerular basement membrane (GBM) and the eventual development of glomerulosclerosis. Other factors that are induced by the diabetic environment which could influence glomerular hemodynamics are vascular endothelial growth factor-A (VEGF-A), perhaps via production of NO, and even cytokines such as transforming growth factor-β1 (TGF-β1) which may mediate hyperfiltration by arteriolar vasodilatation via inhibiting calcium transients [2, 3]. Furthermore, TGF-β1 increases NO production in early diabetes, presumably by upregulation of endothelial NO synthase (eNOS) mRNA expression and enhancing arginine resynthesis [3].…”

Section: Hemodynamic Changesmentioning

confidence: 99%

“…Other factors that are induced by the diabetic environment which could influence glomerular hemodynamics are vascular endothelial growth factor-A (VEGF-A), perhaps via production of NO, and even cytokines such as transforming growth factor-β1 (TGF-β1) which may mediate hyperfiltration by arteriolar vasodilatation via inhibiting calcium transients [2, 3]. Furthermore, TGF-β1 increases NO production in early diabetes, presumably by upregulation of endothelial NO synthase (eNOS) mRNA expression and enhancing arginine resynthesis [3]. Thus, TGF-β1 could clearly play a role in diabetic vascular dysfunction and may mediate some of the hemodynamic changes associated with early diabetic nephropathy [3].…”

Section: Hemodynamic Changesmentioning

confidence: 99%

“…Furthermore, TGF-β1 increases NO production in early diabetes, presumably by upregulation of endothelial NO synthase (eNOS) mRNA expression and enhancing arginine resynthesis [3]. Thus, TGF-β1 could clearly play a role in diabetic vascular dysfunction and may mediate some of the hemodynamic changes associated with early diabetic nephropathy [3]. On the other hand, shear stress and mechanical strain, resulting from altered glomerular hemodynamics, induce autocrine and/or paracrine release of cytokines and growth factors.…”

Section: Hemodynamic Changesmentioning

confidence: 99%

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Cellular and Molecular Mechanisms of Proteinuria in Diabetic Nephropathy

2007

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One of the earliest clinically detectable abnormalities in diabetic nephropathy is microalbuminuria that eventually progresses to proteinuria. The degree of proteinuria correlates with the progression of glomerulosclerosis and tubulointerstitial fibrosis. In the glomerulus, a typical podocytopathy develops that participates in the initiation of glomerulosclerosis and the accelerated plasma protein leakage across the glomerular basement membrane (GBM) into Bowman’s space. Downstream into the tubular compartment, the proteinuria induces proinflammatory and profibrogenetic injury in tubular cells which can facilitate the development of interstitial fibrosis and tubular atrophy. It has long been held that hemodynamic changes and the loss of negatively charged proteoglycans in the GBM are important mediators of proteinuria. More recently, biopsy studies in humans with diabetic kidney disease have provided strong evidence that podocytes are injured very early in the course of nephropathy. This podocytopathy – which is characterized by decreased podocyte number and/or density, GBM thickening and altered matrix composition, and foot process effacement – correlates closely with the development and progression of albuminuria. Components of the diabetic milieu (high glucose, accumulation of glycated proteins, high intrarenal angiotensin II (ANG II), and hypertension-induced mechanical stress) result in activation of cytokine systems, the most important of which are transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor-A (VEGF-A). ANG II-stimulated podocyte-derived VEGF, through a novel autocrine signaling loop, appears to be a major cause of nephrin downregulation and the development of proteinuria. Nephrin is an important protein of the slit diaphragm with anti-apoptotic signaling properties. TGF-β1 causes podocyte apoptosis and an increase in extracellular matrix deposition. As a consequence, the denuded GBM adheres to Bowman’s capsule initiating the development of glomerulosclerosis. Good control of hyperglycemia and hypertension and maximal inhibition of ANG II are essential steps in preventing the development and progression of diabetic nephropathy.

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Section: Hemodynamic Changesmentioning

confidence: 99%

Section: Hemodynamic Changesmentioning

confidence: 99%

Section: Hemodynamic Changesmentioning

confidence: 99%

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Cellular and Molecular Mechanisms of Proteinuria in Diabetic Nephropathy

2007

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“…1,[3][4][5] There is evidence from cell cultures, animal models, and clinical studies that TGF-␤ is a primary mediator of the fibrogenic effects of hyperglycemia in diabetic nephropathy. 6,7 Elevated TGF-␤ activity also has a role in podocyte dysfunction, including epithelial mesenchymal transition of the podocyte with loss of slit diaphragm proteins associated with the filtration barrier, such as nephrin, and, ultimately, podocyte apoptosis at higher TGF-␤ concentrations.…”

mentioning

confidence: 99%

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Miao

Schoeb

et al. 2011

The American Journal of Pathology

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Transforming growth factor-␤ (TGF-␤) is key in the pathogenesis of diabetic nephropathy. Thrombospondin 1 (TSP1) expression is increased in diabetes, and TSP1 regulates latent TGF-␤ activation in vitro and in diabetic animal models. Herein, we investigate the effect of blockade of TSP1-dependent TGF-␤ activation on progression of renal disease in a mouse model of type 1 diabetes (C57BL/6J-Ins2 Akita ) as a targeted treatment for diabetic nephropathy. Akita and control C57BL/6 mice who underwent uninephrectomy received 15 weeks of thrice-weekly i.p. treatment with 3 or 30 mg/kg LSKL peptide, control SLLK peptide, or saline. The effects of systemic LSKL peptide on dermal wound healing was assessed in type 2 diabetic mice (db/db). Proteinuria (urinary albumin level and albumin/creatinine ratio) was significantly improved in Akita mice treated with 30 mg/kg LSKL peptide. LSKL treatment reduced urinary TGF-␤ activity and renal phospho-Smad2/3 levels and improved markers of tubulointerstitial injury (fibronectin) and podocytes (nephrin). However, LSKL did not alter glomerulosclerosis or glomerular structure. LSKL did not increase tumor incidence or inflammation or impair diabetic wound healing. These data suggest that selective targeting of excessive TGF-␤ activity through blockade of TSP1-dependent TGF-␤ activation represents a therapeutic strategy for treating diabetic nephropathy that preserves the homeostatic functions of TGF-␤.

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“…Furthermore, TGF-increases NO production in early diabetes, probably by up-regulation of endothelial NO synthase (eNOS) mRNA expression and by enhancing arginine resynthesis [72]. Thus, TGFcould clearly play a role in diabetic vascular dysfunction [74].…”

Section: Hemodynamic Abnormalitiesmentioning

confidence: 99%