Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of alpha-smooth muscle actin-positive myofibroblast cells is a key event in the progression of chronic renal diseases that leads to end-stage renal failure. Although the origin of these myofibroblasts in the kidney remains uncertain, emerging evidence suggests that renal myofibroblasts may derive from tubular epithelial cells by a process of epithelial to mesenchymal transition. It was demonstrated that hepatocyte growth factor (HGF) exhibited a remarkable ability to block this phenotypic transition both in vitro and in vivo. HGF abrogated the alpha-smooth muscle actin expression and E-cadherin depression triggered by transforming growth factor-beta1 in tubular epithelial cells in a dose-dependent manner. HGF also blocked morphologic transformation of tubular epithelial cells and inhibited the expression and extracellular deposition of fibronectin. In a mouse model of renal fibrosis disease induced by unilateral ureteral obstruction, transforming growth factor-beta type I receptor expression was specifically increased in renal tubules, and myofibroblastically phenotypic transition of the tubules was evident in vivo. Remarkably, injections of exogenous HGF blocked myofibroblast activation and drastically prevented renal interstitial fibrosis in the obstructed kidneys. These results suggest that tubular epithelial to myofibroblast conversion may play an important role in the pathogenesis of renal fibrosis and that blocking this phenotypic transition could provide a novel therapeutic strategy for the treatment of fibrotic diseases.
 ...
PMID:Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. 1175 26

Familial non-immune-mediated glomerulopathy has recently been recognized as a distinct clinical entity. The presentation includes proteinuria, often in the nephrotic range, microscopic hematuria, and hypertension. Renal function may remain intact long term, or may progress slowly to renal failure. A 3-year-old boy was referred with proteinuria (>8 g/day), microscopic hematuria, and hypertension (184/150 mmHg). Renal function was intact. Diagnostic evaluation uncovered no evidence of systemic disease. A renal biopsy specimen showed no immune deposits in the glomeruli, but fibronectin deposits were detected in the peripheral loop and mesangium by immunofluorescence. The basement membrane was intact. Twelve other family members subsequently were found to have some renal pathology. Renal function was preserved during 7 years of follow-up. The pathogenesis of fibronectin glomerulopathy is discussed.
 ...
PMID:Fibronectin glomerulopathy with nephrotic syndrome in a 3-year-old male. 1204 95

Alteration in renal glomerular mesangial cell growth and fibronectin matrix deposition is a hallmark of glomerulosclerosis, which ultimately leads to end-stage renal failure. We have previously shown that the expression of integrin-linked kinase (ILK), a cytoplasmic component of the cell-extracellular matrix contacts, is increased in mesangial cells in human patients with diabetic nephropathy. We show here that ILK forms a complex with PINCH and CH-ILKBP in primary mesangial cells, which are co-clustered at fibrillar adhesions, sites that are involved in fibronectin matrix deposition. To investigate functional significance of the PINCH-ILK-CH-ILKBP complex formation, we expressed the PINCH-binding N-terminal fragment and the CH-ILKBP-binding C-terminal fragment of ILK, respectively, in mesangial cells by using an adenoviral expression system. Overexpression of either the N-terminal fragment or the C-terminal fragment of ILK effectively inhibited the PINCH-ILK-CH-ILKBP complex formation. Inhibition of the PINCH-ILK-CH-ILKBP complex formation significantly reduced fibronectin matrix deposition and inhibited cell proliferation. These results indicate that the PINCH-ILK-CH-ILKBP complex is critically involved in the regulation of mesangial fibronectin matrix deposition and cell proliferation, and suggest that it may potentially serve as a useful target in the therapeutic control of progressive renal failure and other pathological processes involving abnormal cell proliferation and fibronectin matrix deposition.
 ...
PMID:Regulation of fibronectin matrix deposition and cell proliferation by the PINCH-ILK-CH-ILKBP complex. 1206 Jun 75

Calcitriol, 1,25(OH)(2)D(3), has been reported to have a beneficial effect on bone histology in patients with predialysis chronic renal failure; however, such treatment involves a risk of hypercalcemia. To investigate the effects of 1,25(OH)(2)D(3) and 22-oxacalcitriol (OCT) on the progression of histologic deterioration, we administered intraperitoneal 1,25(OH)(2)D(3) or OCT, three times a week, to rats with adriamycin-induced progressive renal failure, from the 10th week after the induction of ADR-induced nephropathy. The rats were divided into the following groups: (1) high-dose 1,25(OH)(2)D(3), 0.2 microg/kg (group D(3)-0.2); (2) low-dose 1,25(OH)(2)D(3), 0.04 microg/kg (group D(3)-0.04); (3) high-dose OCT, 0.2 microg/kg (group OCT-0.2); (4) low-dose OCT, 0.04 microg/kg (group OCT-0.04); and (5) ADR-induced nephropathy (group ADR). The death rate at week 20 in group D(3)-0.2 was 50%, significantly higher than the death rates in the other groups, except for group D(3)-0.04 (P <.05). The serum creatinine and blood urea nitrogen levels were the highest in group D(3)-0.2, although the difference was not significant. In contrast, in groups OCT-0.2 and OCT-0.04, tubular changes and interstitial volume were smaller than in groups D(3)-0.2 and D(3)-0.04 (P <.05). Although calcium deposits increased in group D(3)-0.2, the difference was not significant. Glomerular expression of transforming growth factor-beta1 (TGF-beta1) expression was less in groups OCT-0.2 and OCT-0.04 than in groups D(3)-0.2 and D(3)-0.04 (P <.05). Glomerular fibronectin expression was less in group OCT-0.2 than in groups D(3)-0.2 and ADR (P <.05). Tubulointerstitial expression of TGF-beta1 was greater in group D(3)-0.2 than in group ADR and greater in group D(3)-0.04 than in group OCT-0.04 (P <.05). We conclude that a high dose of 1,25(OH)(2)D(3) accelerated the progressive renal deterioration of ADR-induced nephropathy, and, as a result, OCT was able to attenuate renal histologic lesions.
 ...
PMID:Different effects of 22-oxacalcitriol and calcitriol on the course of experimental chronic renal failure. 1238 22

Reflux nephropathy (RN) is the cause of end-stage renal failure in 3%-25% of children and 10%-15% of adults. Angiotensin-converting enzyme (ACE) converts the inactive decapeptide angiotensin I (Ang I) to the active octapeptide angiotensin II (Ang II), a potent vasoconstrictor. ACE is localized in highest concentrations on the luminal surface of endothelial cells, but is also found in several other cell types, including the epithelial cells of the proximal renal tubule. Recent studies have suggested that ACE increases production of the components of extracellular matrix (ECM) such as fibronectin (Fib) mediated through Ang II. Since RN is a primary tubulointerstitial disease, we hypothesized that local overexpression of ACE may induce renal fibrosis via up-regulation of Ang II. In this study, we investigated the expression of ACE in severely refluxing kidneys from eight patients (age range 6 months-14 years) with severe RN secondary to primary high-grade vesicoureteral reflux at nephrectomy. Control material included normal kidney specimens obtained from three adult patients during partial nephrectomy for an incidentaloma. Soluble enzyme immunohistochemistry was carried out using polyclonal antibodies to ACE and Fib. In-situ hybridization (ISH) was performed utilizing biotin-labelled antisense oligonucleotide probe. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate the relative amount of ACE mRNA. In the refluxing kidney, there was strong ACE immunoreactivity in the glomerulus and proximal tubules and moderate-to-strong immunoreactivity in the distal tubules accompanied by strong Fib immunoreactivity in the glomerulus, proximal tubule, and interstitial space. There was strong ACE mRNA expression in the glomerulus and proximal tubules and moderate expression in the distal tubules. In the control kidneys, homogeneous weak ACE immunoreactivity and mRNA expression was demonstrated only in the proximal tubules. RT-PCR showed strong ACE expression in the refluxing kidneys compared to controls. Up-regulation of ACE in RN accompanied by an increase in ECM in the tubulointerstitial space suggests that ACE is involved in the pathogenesis of the renal parenchymal damage in patients with RN. Pharmacologic blockade of ACE may be helpful in preventing the renal fibrosis associated with RN.
 ...
PMID:Up-regulation of angiotensin-converting enzyme (ACE) gene expression induces tubulointerstitial injury in reflux nephropathy. 1247 81

The expression of fibronectin (FN), one of the extracellular matrix proteins, was studied in isolated renal proximal tubules in a in vivo rat model of unilateral renal ischemia without reperfusion. FN is involved in cell-extracellular matrix interactions and defective cell-extracellular matrix interactions have been hypothesized to contribute to ischemic renal failure. The expression of FN was investigated by reverse transcription-polymerase chain reaction (RT-PCR), Elisa and Western blot. Isolated proximal tubules from control and post-ischemic rat kidneys were used. ATP, intracellular calcium content, and alkaline phosphatase were also measured to describe the effects associated to 40 min of ischemia. Control tubules expressed FN. Forty minutes of ischemia promoted diminished ATP levels and phosphatase alkaline activity, and increased intracellular calcium in isolated proximal tubules. An increased abundance of FN was observed by ischemic tubules as compared with control tubules. To determine quantitatively the value of FN content, ELISA method was performed. The ischemic tubules also expressed higher amount of FN mRNA. Three amplification products were obtained from both ischemic and control proximal tubular cDNA. The relative amounts of each of the obtained products were the same, strongly suggesting that the augmentation of the FN gene transcription during ischemia is not associated to a modification in the splicing pattern. Moreover, this expression is increased after 40 min of ischemia, not followed by reperfusion.
 ...
PMID:Fibronectin expression in proximal tubules from ischemic rat kidneys without reperfusion. 1248 21

Tubulointerstitial fibrosis is a hallmark feature of chronic renal injury. Specific therapies to control the progression of renal fibrosis toward end-stage renal failure are limited. Previous studies have demonstrated that expression of endogenous bone morphogenic protein-7 (BMP-7) is reduced in the kidneys of several inducible mouse models of acute and chronic renal disease and that administration of exogenous recombinant human BMP-7 (rhBMP-7) has a beneficial effect on kidney function. Here we report that treatment with rhBMP-7 leads to improved renal function, histology, and survival in mice deficient in the alpha3-chain of type IV collagen and MRL/MpJlpr/lpr lupus mice, two genetic models for chronic renal injury and fibrosis. Such therapeutic benefit is also associated with a significant decrease in the expression of profibrotic molecules, such as type I collagen and fibronectin, in renal fibroblasts. Additionally, rhBMP-7 induces expression of active matrix metalloproteinase-2, which is potentially important for removal of fibrotic matrix. Collectively, these studies provide further evidence for rhBMP-7 as an important bone-associated protein with protective function against renal pathology.
 ...
PMID:Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. 1291 82

Diabetic nephropathy affects 30-40% of diabetics leading to end-stage kidney failure through progressive scarring and fibrosis. Previous evidence suggests that tissue transglutaminase (tTg) and its protein cross-link product epsilon(gamma-glutamyl)lysine contribute to the expanding renal tubulointerstitial and glomerular basement membranes in this disease. Using an in vitro cell culture model of renal proximal tubular epithelial cells we determined the link between elevated glucose levels with changes in expression and activity of tTg and then, by using a highly specific site directed inhibitor of tTg (1,3-dimethyl-2[(oxopropyl)thio]imidazolium), determined the contribution of tTg to glucose-induced matrix accumulation. Exposure of cells to 36 mm glucose over 96 h caused an mRNA-dependent increase in tTg activity with a 25% increase in extracellular matrix (ECM)-associated tTg and a 150% increase in ECM epsilon(gamma-glutamyl)lysine cross-linking. This was paralleled by an elevation in total deposited ECM resulting from higher levels of deposited collagen and fibronectin. These were associated with raised mRNA for collagens III, IV, and fibronectin. The specific site-directed inhibitor of tTg normalized both tTg activity and ECM-associated epsilon(gamma-glutamyl)lysine. Levels of ECM per cell returned to near control levels with non-transcriptional reductions in deposited collagen and fibronectin. No changes in transforming growth factor beta1 (expression or biological activity) occurred that could account for our observations, whereas incubation of tTg with collagen III indicated that cross-linking could directly increase the rate of collagen fibril/gel formation. We conclude that Tg inhibition reduces glucose-induced deposition of ECM proteins independently of changes in ECM and transforming growth factor beta1 synthesis thus opening up its possible application in the treatment other fibrotic and scarring diseases where tTg has been implicated.
 ...
PMID:Inhibition of transglutaminase activity reduces extracellular matrix accumulation induced by high glucose levels in proximal tubular epithelial cells. 1532 85

The expression of nephropathy in type 2 diabetes has several levels of abnormalities. To define the primary abnormalities of diabetic nephropathy, we conducted an autopsy study of 186 consecutive patients with type 2 diabetes to determine correlations among the aldose reductase gene, renal histopathologies, extracellular matrix, glomerular function, and clinical characteristics. Compared with cases of near-normal renal structure (n = 51) and atypical diabetic glomerulopathy (n = 75), patients with classic diabetic glomerulopathy (n = 60) had advanced glomerular disease, as reflected by elevated plasma creatinine levels (133.2 +/- 59.8 vs. 166.0 +/- 65.7 vs. 243.8 +/- 82.6 micromol/l; P < 0.001), glomerular matrix fractions (20.8 +/- 6.7 vs. 33.5 +/- 16.8 vs. 39.2 +/- 14.3%; P < 0.001), and risk of renal failure (odds ratio [OR] 1 vs. 3.5 vs. 21.4; P < 0.001). Compared with noncarriers of the aldose reductase z-2 allele (n = 92) and z-2 heterozygotes (n = 77), z-2 homozygotes (n = 17) had elevated plasma creatinine (164.1 +/- 73.7 vs. 190.6 +/- 60.9 vs. 241.1 +/- 86.2 micromol/l; P < 0.001) and an increased risk of classic diabetic glomerulopathy (OR 1 vs. 0.9 vs. 3.3; P = 0.026). Overexpression of transforming growth factor-beta1, mesangial cell transdifferentiation by expression of alpha-smooth muscle actin, and aberrant deposition of collagen type IV, fibronectin, and laminin were found in classic diabetic glomerulopathy. These data suggest genetic, biochemical, pathophysiological, and clinical correlations among the aldose reductase gene, extracellular matrix, classic diabetic glomerulopathy, and renal insufficiency. Gene mutation, cellular transdifferentiation, growth factor upregulation, extracellular matrix expansion, and glomerular filtration impairment are the primary abnormalities in type 2 diabetic patients with nephropathy.
 ...
PMID:Association of glomerulopathy with the 5'-end polymorphism of the aldose reductase gene and renal insufficiency in type 2 diabetic patients. 1550 80

Tubulointerstitial fibrosis (TIF) is thought now to be a key factor in progression of renal failure in chronic nephropathies. A similar pattern of changes in glomerulonephritis and amyloidosis suggests common mechanisms operating in progression of renal failure in these nephropathies. Of importance in the process of interstitial inflammation is activation of the nuclear factor of transcription (NFkB) in tubular cells due to components of proteinuria and their secretion of some proinflammatory mediators, first of all chemokines with formation of inflammatory infiltrate and accumulation of interstitial myofibroblasts--the main source of extracellular matrix (ECM) components. Our findings are of interest in the light of current ideas that among ECM components the number of fibronectin deposites most of all reflects the severity of structural renal tissue damage including TIF and correlates with severity of renal failure.
 ...
PMID:[The key role of tubulointerstitium remodeling in progression of chronic renal diseases]. 1564 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>