Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy.

Abstract

Diabetes is now the most common cause of progressive kidney failure leading to dialysis or transplantation. The central pathological feature of diabetic nephropathy is accumulation of extracellular matrix within the glomeruli. The factors in the diabetic milieu responsible for extracellular matrix accumulation are not understood. Here we report that in glomeruli of rats made diabetic there is a slow, progressive increase in the expression of transforming growth factor 1B (TGF-3) mRNA and TGF-,3 protein. A key action of TGF-,B is induction of extraceliular matrix production, and specific matrix proteins known to be induced by TGF-(3 were increased in diabetic rat glomeruli. These proteins include an alternatively spliced form of fibronectin, tenascin, and the proteoglycan biglycan. TGF-f8 has not previously been implicated in the matrix accumulation that occurs in the diabetic kidney. Glomeruli from humans with diabetic nephropathy also showed a striking increase in immunoreactive TGF-,B protein and deposition of the special form of fibronectin, whereas glomeruli from normal subjects or from individuals with other glomerular diseases (where extracellular matrix accumulation is not a feature) were negative or barely positive. These results implicate TGF-13 in the pathogenesis of diabetic nephropathy.Development of kidney disease is one of the most frequent and serious complications of diabetes and eventually occurs in patients despite treatment with insulin (1, 2). The dominant histological feature of diabetic nephropathy is the expansion of extracellular matrix in the mesangial areas of the glomeruli with resulting glomerulosclerosis and obliteration of the capillary surface area for filtration (3,4). Expansion of the mesangial matrix correlates strongly with the clinical onset of proteinuria, hypertension, and kidney failure (3, 4). Diabetes is considered a hormonal disorder, and organ complications such as kidney disease are usually attributed to metabolic consequences of abnormal glucose regulation such as elevated blood and tissue levels of glycosylated proteins (5) and/or hemodynamic changes within the kidney (6). However, whether this hypothesis is correct is unclear, and little is known about the molecular events underlying the matrix accumulation. This report presents evidence for the idea that diabetes can lead to elevated transforming growth factor ,B (TGF-f) expression and that this cytokine may be one cause of matrix deposition in the diabetic kidney.Three isoforms of B,81,82, are expressed in mammals and to date show similar properties in vitro (7). The role of TGF-,3 in regulating repair and regeneration following tissue injury is well documented (8). Platelets contain high concentrations of TGF-/3 and upon degranulation at a site of injury release TGF-P into the surrounding tissue (9). TGF-P then initiates a sequence of events that promotes healing including (i) chemoattraction of monocytes, neutrophils, and fibroblasts (10, 11); (ii) autoinduction ofTGF-f3 production and stimulation of ...

P38 mitogen-activated protein kinase mediates hexosamine-induced TGFβ1 mRNA expression in human mesangial cells

“…Furthermore, in porcine and rat mesangial cells the addition of glucosamine [6,7], a precursor of the HBP, or over-expression of GFAT [8] increases TGFβ1 expression, a key factor in the pathogenesis of diabetic glomerulosclerosis [9,10,11,12,13]. However, there is currently no information on the role of the HBP in the induction of TGFβ1 expression in human renal cells or on the intracellular signalling pathways involved.…”

Angiotensin II induces human TGF-β1 promoter activation: similarity to hyperglycaemia

“…The prosclerotic cytokine transforming growth factor beta (TGF-β1) has been implicated as an important downstream mediator in the progression of the renal pathological changes occurring in diabetic patients which lead to glomerular and tubular basement membrane thickening, mesangial matrix expansion, and glomerulosclerosis [13,15,15,16,17,18]. Numerous studies including data from our own laboratory indiStudies have provided evidence that angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists attenuate diabetic glomerulosclerosis and slow the progression of diabetic kidney disease [1, 2, cate that hyperglycemia induces an increase in TGF-β1 protein and mRNA expression in experimental and human diabetes [15,19,20,21] and in cultured mesangial cells [22,23,24].…”

“…Numerous studies including data from our own laboratory indiStudies have provided evidence that angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists attenuate diabetic glomerulosclerosis and slow the progression of diabetic kidney disease [1, 2, cate that hyperglycemia induces an increase in TGF-β1 protein and mRNA expression in experimental and human diabetes [15,19,20,21] and in cultured mesangial cells [22,23,24]. Although previous investigations clearly demonstrated that ang II stimulates the synthesis of extracellular matrix proteins through an enhanced TGF-β1 expression in mesangial cells [25] the molecular mechanism of ang II-induced TGF-β1 gene activation, particularly the detailed localization of the ang II responsive elements on the TGF-β1 promoter, have not been studied yet.…”

Treatment and impact of dyslipidemia in diabetic nephropathy

“…In addition to this study, a lot of basic research has discovered the mechanisms between dyslipidemia and diabetic nephropathy [14]. Studies revealed that transforming growth factor-b signaling [15], renin-angiotensin system [16], S100A8/TLR4 signaling [17], and oxidative stress [18] may play an important role in the progression of diabetic nephropathies. Concerning the development of albuminuria, the importance of the deterioration of glycocalyx, which is on the surface of endothelium, was highlighted [19].…”