Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis.
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Connective tissue growth factor (CTGF) is one of the candidate factors mediating downstream events of transforming growth factor-beta (TGF-beta), but its role in fibrogenic properties of TGF-beta and in tubulointerstitial fibrosis has not yet been clarified. Using unilateral ureteral obstruction (UUO) in rats, we analyzed gene expression of TGF-beta1, CTGF, and fibronectin. We further investigated the effect of blockade of endogenous CTGF on TGF-beta-induced fibronectin expression in cultured rat renal fibroblasts by antisense oligodeoxynucleotide (ODN) treatment. After UUO, CTGF mRNA expression in the obstructed kidney was significantly upregulated subsequent to TGF-beta1, followed by marked induction of fibronectin mRNA. By in situ hybridization, CTGF mRNA was detected mainly in the interstitial fibrotic areas and tubular epithelial cells as well as in parietal glomerular epithelial cells in the obstructed kidney. The interstitial cells expressing CTGF mRNA were also positive for alpha-smooth muscle actin. CTGF antisense ODN transfected into cultured renal fibroblasts significantly attenuated TGF-beta-stimulated upregulation of fibronectin mRNA and protein compared with control ODN transfection, together with inhibited synthesis of type I collagen. With the use of a reporter assay, rat fibronectin promoter activity was increased by 2.5-fold with stimulation by TGF-beta1, and this increase was abolished with antisense CTGF treatment. Thus CTGF plays a crucial role in fibronectin synthesis induced by TGF-beta, suggesting that CTGF blockade could be a possible therapeutic target against tubulointerstitial fibrosis. (+info)
Gene expression profile of renal proximal tubules regulated by proteinuria.
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BACKGROUND: Proximal tubules activated by reabsorption of protein are thought to play significant roles in the progression of kidney diseases. Thus, identification of genes related to proteinuria should provide insights into the pathological process of tubulointerstitial fibrosis. METHOD: Gene expression profiles were constructed by means of direct sequencing procedures to identify genes induced in the mouse kidney proximal tubules (PT) exposed to proteinuria. RESULTS: By comparing the gene expression of control PT to that of disease model PT, the abundantly expressed genes in control PT were down-regulated presumably because of potentially toxic effects of proteinuria. From the more than 1000 up-regulated genes, an immunity related gene, thymic shared antigen-1 (TSA-1), and a novel gene, GS188, were selected for further characterization. The increased expression of TSA-1, a member of the Ly-6 family, and of GS188 in response to proteinuria was confirmed by Northern analysis, immunohistochemistry, in situ hybridization and laser microdissection along with real-time PCR analysis. Full length cloning of GS188 identified it as a family member of LR8 that was reported to express predominantly in fibroblasts. CONCLUSIONS: The gene expression profiles showed that the expression patterns in PT were changed dramatically by proteinuria. The profiles include novel genes that should be further characterized to aid the understanding of the pathophysiology of progressive kidney diseases. (+info)
Transferrin up-regulates chemokine synthesis by human proximal tubular epithelial cells: implication on mechanism of tubuloglomerular communication in glomerulopathic proteinura.
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BACKGROUND: The pathogenesis of glomerulosclerosis and tubulointerstitial fibrosis in proteinuric renal disease is obscure. We recently showed that transferrin, a key proteinuric component, mediates proximal tubular epithelial cell (PTEC) C3 synthesis. To further examine whether proteinuric tubular injury may induce glomerular inflammation and to characterize the role of transferrin in activating PTEC, glomerular mesangial cells (MC) were exposed to transferrin-activated PTEC culture supernatant and their proliferative and profibrotic responses analyzed. METHODS: Human PTEC and MC were obtained by primary culture. Confluent, transferrin-stimulated PTEC were grown in serum-free medium to produce a "conditioned" medium that was incubated with quiescent MC. The proliferative response of MC was then assessed by thymidine uptake, and the expression of fibrogenic factors measured by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The chemokine profile in PTEC after transferrin treatment was examined by RT-PCR and ELISA. RESULTS: "Conditioned" supernatant from PTEC, which contained the highest amounts of platelet-derived growth factor (PDGF), stimulated MC proliferation compared with serum-free (P = 0.03) or transferrin-containing (P = 0.009) control media. This proliferative response was partially abrogated by treating MC with anti-PDGF. MC expression of PDGF, but not transforming growth factor-beta or intercellular cell adhesion molecule-1, was up-regulated by conditioned PTEC medium. Transferrin up-regulated monocyte chemoattractant peptide-1, interleukin-8, and macrophage migration inhibitory factor expression in a time- and dose-dependent fashion, but had no effect on RANTES expression by PTEC. CONCLUSIONS: These results provide experimental evidence suggesting that there is a tubuloglomerular "cross-talk" mechanism in the proteinuric state. PTEC-secreted PDGF, which further induces mesangial PDGF, could partially account for the mesangial proliferation frequently observed in proteinuric renal disease. Transferrin is one of the culprit nephrotic proteins leading to tubular overexpression of various proinflammatory chemokines, which may explain the interstitial changes observed in proteinuric states. (+info)
Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction.
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BACKGROUND: The small GTPase Rho is involved in cell-to-substratum adhesion and cell contraction. These actions of Rho mediated by downstream Rho effectors such as Rho-associated coiled-coil forming protein kinase (ROCK) may be partly responsible for the progression of renal interstitial fibrosis. METHODS: The anti-fibrosis effects of Y-27632, a specific ROCK inhibitor, were studied both in vivo (unilateral ureteral obstruction; UUO) and in vitro. To investigate the therapeutic efficacy of Y-27632 in UUO kidneys, smooth muscle alpha actin (SMalphaA) expression, macrophage infiltration and fibrosis in the obstructed kidneys were studied. SMalphaA, transforming growth factor beta (TGF-beta), alpha1 (I) collagen, osteopontin, macrophage chemoattractant peptide-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) gene expression were examined by Northern blotting. To elucidate the mechanism linking the Rho-ROCK pathway with renal fibrosis, the effects of Y-27632 on in vitro cell proliferation and cell migration were studied. RESULTS: In vivo analysis showed that Y-27632 suppressed SMalphaA expression, macrophage infiltration and interstitial fibrosis, and that Y-27632 suppressed SMalphaA, TGF-beta and alpha1 (I) collagen mRNA expression. In vitro analysis showed that Y-27632 did not suppress proliferation of renal fibroblasts but suppressed migration of macrophages. CONCLUSIONS: The Rho-ROCK system may play an important role in the development of tissue fibrosis, and the Rho-ROCK signaling pathway may be a new therapeutic target for preventing interstitial fibrosis in progressive renal disease. (+info)
Risk factors for cyclosporine-induced tubulointerstitial lesions in children with minimal change nephrotic syndrome.
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BACKGROUND: Cyclosporine (CsA) is effective for the treatment of children with steroid-dependent and -resistant nephrotic syndrome (NS), but it can result in chronic CsA nephrotoxicity including CsA-induced tubulointerstitial lesions. The factors responsible for the development of CsA-induced tubulointerstitial lesions are unknown. METHODS: To identify the risk factors for the development of CsA-induced tubulointerstitial lesions in children with minimal change NS who had been treated with long-term moderate-dose CsA, we compared several clinical and laboratory factors of 37 patients with and without CsA-induced tubulointerstitial lesions by the Mann-Whitney U test, Fisher's exact test, and stepwise logistic-regression analysis. RESULTS: Thirteen patients had CsA-induced tubulointerstitial lesions and 24 patients had none. Among clinical and laboratory factors, the duration of CsA treatment (P = 0.003) and the duration of heavy proteinuria during CsA treatment (P = 0.024) were related to the development of CsA-induced tubulointerstitial lesions as determined by the univariate analyses. Indeed, CsA-induced tubulointerstitial lesions were found in 2 of 18 (11%) patients who had been treated with CsA for less than 24 months, but in 11 of 19 patients (58%) who had been treated for more than 24 months (P = 0.005). They were also found in 4 of 23 patients (17%) who had heavy proteinuria for less than 30 days during CsA treatment, but in 9 of 14 patients (64%) who had heavy proteinuria for more than 30 days (P = 0.006). Stepwise logistic-regression analysis revealed that the duration of CsA treatment for more than 24 months (chi2 = 6.203, P = 0.013) and the duration of heavy proteinuria during CsA treatment for more than 30 days (chi2 = 5.871, P = 0.015) were independent risk factors for the development of CsA-induced tubulointerstitial lesions. CONCLUSIONS: Duration of the CsA treatment and the duration of heavy proteinuria during CsA treatment were independent significant risk factors for the development of CsA-induced tubulointerstitial lesions in children with MCNS who had been treated with long-term moderate-dose CsA. (+info)
Participation of different macrophage populations and myofibroblastic cells in chronically developed renal interstitial fibrosis after cisplatin-induced renal injury in rats.
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To shed some light on the mechanisms behind renal fibrogenesis, the present study immunohistochemically investigated the participation of different macrophage populations and myofibroblastic cells in rat renal interstitial fibrosis developed chronically after repeated injection of cisplatin (2 mg/kg body weight, once weekly for 7 weeks). During the 19-week recovery period after the final injection, fibrotic lesions progressively developed in the corticomedullary junction, with the greatest level at post-final injection (FPI) week 5, and then the lesions were gradually repaired by PFI week 19, indicative of a healing process. In conformity with the development of fibrotic lesions, the number of myofibroblastic cells reacting with an anti-alpha-smooth muscle actin antibody was increased, with a peak at PFI week 3, and collagens (types I, III, and IV), fibronection, and laminin were excessively accumulated in these areas. Interstitial cells forming the fibrotic lesions showed mitotic activity at the early stages, whereas they disappeared by apoptosis in the healing process. A large number of cells reacting with an antibody of ED1 (for exudate macrophages), ED2 (for resident macrophages), or OX6 (for major histocompatibility complex class II-presenting macrophages and interstitial dendritic cells) had already appeared at PF1 week 1, and then their numbers increased, with a peak at PFI weeks 7, 3, and 9 in ED1-, ED2-, and OX6-positive cells, respectively. Thereafter, the number of ED1- and ED2-positive cells decreased, whereas the number of OX6-positive cells persisted at a high level until PFI week 19. In the healing process, clusters of lymphocytes were present, the development of which might have been related to OX6-positive cells. The present study demonstrated that chronically developing rat renal interstitial fibrosis might be produced by the complicated mechanisms evoked by interactions between different macrophage populations and myofibroblastic cells, because macrophages show heterogeneous functions depending on microenvironmental factors. (+info)
European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.2.4. Chronic graft dysfunction. De novo renal disease after transplantation.
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GUIDELINES: A. Acute pyelonephritis is relatively frequent in the transplanted kidney and carries a risk of septicaemia. The condition should be recognized and the patient should be treated promptly in the hospital. B. After initiation of any drugs known to induce the development of interstitial nephritis in the transplant patient, it is recommended to monitor renal function and abnormalities in order to detect any side effects rapidly. If interstitial nephritis is observed, it is recommended to stop the offending drug, and to initiate appropriate treatment. C. De novo membranous nephropathy should be considered in cases of proteinuria and nephrotic syndrome after transplantation. Viral infection, such as HCV, should be excluded. D. In the case of the development of graft dysfunction in a transplant patient with Alport's syndrome, one should consider additionally the possibility of de novo anti-glomerular basement membrane (anti-GBM) glomerulonephritis. (+info)
Aristolochic acid as a probable human cancer hazard in herbal remedies: a review.
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The old herbal drug aristolochic acid (AA), derived from Aristolochia spp., has been associated with the development of a novel nephropathy, designated aristolochic acid nephropathy (AAN), and urothelial cancer in AAN patients. There is clear evidence that the major components of the plant extract AA, aristolochic acid I (AAI) and aristolochic acid II (AAII), both nitrophenanthrene carboxylic acids, are genotoxic mutagens forming DNA adducts after metabolic activation through simple reduction of the nitro group. Several mammalian enzymes have been shown to be capable of activating both AAI and AAII in vitro and in cells. The activating metabolism has been elucidated and is consistent with the formation of a cyclic nitrenium ion with delocalized charge leading to the preferential formation of purine adducts bound to the exocyclic amino groups of deoxyadenosine and deoxyguanosine. The predominant DNA adduct in vivo, 7-(deoxyadenosin-N(6)-yl)aristolactam I (dA-AAI), which is the most persistent of the adducts in target tissue, is a mutagenic lesion leading to AT-->TA transversions in vitro. This transversion mutation is found at high frequency in codon 61 of the H-ras oncogene in tumours of rodents induced by AAI, suggesting that dA-AAI might be the critical lesion in the carcinogenic process in rodents. DNA-binding studies confirmed that both AAs bind to the adenines of codon 61 in the H-ras mouse gene and preferentially to purines in the human p53 gene. In contrast, the molecular mechanism of renal interstitial fibrosis in humans after chronic administration of AA remains to be explored. However, preliminary findings suggest that DNA damage by AA is not only responsible for the tumour development but also for the destructive fibrotic process in the kidney. It is concluded that there is significant evidence that AA is a powerful nephrotoxic and carcinogenic substance with an extremely short latency period, not only in animals but also in humans. In particular, the highly similar metabolic pathway of activation and resultant DNA adducts of AA allows the extrapolation of carcinogenesis data from laboratory animals to the human situation. Therefore, all products containing botanicals known to or suspected of containing AA should be banned from the market world wide. (+info)