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Tubulointerstitial Fibrosis (tubulointerstitial + fibrosis)
Selected AbstractsRELATIONSHIP BETWEEN MYOFIBROBLAST APOPTOSIS AND GROWTH FACTORS IN THE PATHOGENESIS OF RENAL TUBULOINTERSTITIAL FIBROSISNEPHROLOGY, Issue 3 2000Lane Ac [source] Renal, vascular and cardiac fibrosis in rats exposed to passive smoking and industrial dust fibre amositeJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 11-12 2009Peter Boor Abstract Passive smoking is an independent risk factor for cardiovascular diseases. Industrial fibrous dust, e.g. the asbestos group member, amosite, causes lung cancer and fibrosis. No data are available on renal involvement after inhalational exposure to these environmental pollutants or of their combination, or on cardiovascular and renal toxicity after exposure to amosite. Male Wistar rats were randomized into four groups (n= 6): control and amosite group received initially two intratracheal instillations of saline and amosite solution, respectively. Smoking group was subjected to standardized daily exposure to tobacco smoke for 2 hrs in a concentration resembling human passive smoking. Combined group was exposed to both amosite and cigarette smoke. All rats were killed after 6 months. Rats exposed to either amosite or passive smoking developed significant glomerulosclerosis and tubulointerstitial fibrosis. Combination of both exposures had additive effects. Histomorphological changes preceded the clinical manifestation of kidney damage. In both groups with single exposures, marked perivascular and interstitial cardiac fibrosis was detected. The additive effect in the heart was less pronounced than in the kidney, apparent particularly in changes of vascular structure. Advanced oxidation protein products, the plasma marker of the myeloperoxidase reaction in activated monocytes/macrophages, were increased in all exposed groups, whereas the inflammatory cytokines did not differ between the groups. In rats, passive smoking or amosite instillation leads to renal, vascular and cardiac fibrosis potentially mediated via increased myeloperoxidase reaction. Combination of both pollutants shows additive effects. Our data should be confirmed in subjects exposed to these environmental pollutants, in particular if combined. [source] Urinary proteins from patients with nephrotic syndrome alters the signalling proteins regulating epithelial,mesenchymal transitionNEPHROLOGY, Issue 1 2010QIONG WEN ABSTRACT: Aim: Proteinuria plays an important role in the progression of tubulointerstitial fibrosis, but the mechanism for the differential renal damage induced by proteinuria is unknown. This study examined the effects of urinary proteins from patients with idiopathic minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) on several epithelial,mesenchymal transition (EMT)-related marker proteins in cultured proximal tubular HK-2 cells. Methods: Urinary proteins from MCD and FSGS patients were extracted by ultrafiltration and incubated with HK-2 cells; the expression of the cytokeratin-18, ,-smooth muscle actin (,-SMA) and vimentin were assessed. p38 and extracellular regulated kinase (ERK) activation were measured by western blotting, and SB203580 (a p38 inhibitor) and PD98059 (an ERK1/2 inhibitor) were used to inhibit their activation. Results: It was observed that urinary proteins from FSGS patients more significantly induced the expression of ,-SMA and vimentin and reduced cytokeratin-18 expression than those from MCD patients in HK-2 cells. Both ERK1/2 and p38 were activated by urinary proteins from MCD or FSGS patients. Pretreatment of the cells with SB203580 or PD98059 abolished the effect of urinary proteins from FSGS patients on the expression of ,-SMA, vimentin and cytokeratin-18, while only SB203580 elicited this effect when cells were treated with urinary proteins from MCD patients. Conclusion: The urinary proteins from MCD and FSGS patients induced significant changes of EMT-related proteins through activation of distinct mitogen-activated protein kinase-related signalling pathways. Quality of proteinuria may play an important role in determining the severity and progression of tubular injury associated with different kidney diseases. [source] Effect of activin A on tubulointerstitial fibrosis in diabetic nephropathyNEPHROLOGY, Issue 3 2009XIAO-JUN REN SUMMARY Aim: The effect of activin A on tubulointerstitial fibrosis in diabetic nephropathy (DN) using streptozotocin (STZ)-induced diabetic rats and high glucose-cultured HK-2 cells was investigated. Methods: Male Wistar rats were randomized into a normal control group (NC) and diabetes mellitus group (DM). Diabetes was induced by i.p. injection of STZ. Six rats were respectively killed 4, 8, 12 and 16 weeks after model establishment in each group. The changes of kidney weight/bodyweight (KW/BW), urine albumin excretion rate (AER) and creatinine clearance rate (Ccr) were determined. The morphology of tubulointerstitium was observed by light microscopy. Further biochemical analysis was provided using immunohistochemistry and real-time polymerase chain reaction. The different parameters in high glucose-cultured HK-2 cells were monitored by western blotting or enzyme-linked immunosorbent assay (ELISA) and the intervention of rh-follistatin on them was investigated. Results: Compared with the NC group, there was marked enlargement in the levels of KW/BW, AER, Ccr and interstitial fibrosis index, and the production of P-Smad2/3 and fibronectin in the DM group from 8 to 16 weeks. Activin ,A, mainly located in tubular epithelial cells, was significantly higher in the DM group than that in the NC group throughout the study periods. Follistatin was abundant in the NC group, but was diminished gradually in the DM group. High glucose may facilitate the synthesis of activin ,A, transforming growth factor (TGF)-,, P-Smad2/3 and fibronectin in HK-2 cells while rh-follistatin inhibited them except TGF-,. Conclusion: Activin A is involved in tubulointerstitial fibrosis in DN by inducing the production of fibronectin through Smad signal pathway. [source] Aldosterone induces collagen synthesis via activation of extracellular signal-regulated kinase 1 and 2 in renal proximal tubulesNEPHROLOGY, Issue 8 2008GUOSHUANG XU SUMMARY: Aim: Aldosterone plays a crucial role in renal fibrosis by inducing mesangial cell proliferation and promoting collagen synthesis in renal fibroblasts. However, renal proximal tubule involvement in aldosterone-induced collagen synthesis has not yet been identified. The aim of this study was to examine the potential role of aldosterone in collagen expression and its possible mineralocorticoid receptor (MR)-dependent pathway, mediated by activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in cultured human renal proximal tubular epithelial (HKC) cells. Methods: After HKC cells were stimulated by aldosterone with different concentrations for various time and periods, the gene expression and protein synthesis of collagen I, II, III and IV were measured by real-time polymerase chain reaction and western blot, respectively. ERK1/2 activation, ,-smooth muscle actin (,-SMA), and E-cadherin were also detected by western blot. Results: Aldosterone can increase ERK1/2 phosphorylation of human renal proximal tubular epithelial cells in a time- and dose-dependent manner. Although aldosterone had no effect on collagen I and II expression, it increased expression of ,-SMA and collagen III and IV and decreased that of E-cadherin in HKC cells after 48 h. These effects could be prevented by a ERK pathway inhibitor, U0126, or by a selective MR antagonist, spironolactone. Conclusion: The results suggest that aldosterone plays a pivotal role in tubulointerstitial fibrosis by promoting tubular epithelial,mesenchymal transition and collagen synthesis in proximal tubular cells. The process is MR-dependent, and mediated by ERK1/2 mitogen-activated protein kinase pathway. [source] Effects of interleukin 18 on injury and activation of human proximal tubular epithelial cellsNEPHROLOGY, Issue 1 2007DONG LIANG SUMMARY: Background/Aims: Injury and activation of tubular proximal epithelial cells (TEC) play central roles in renal tubulointerstitial fibrosis (TIF), but its mechanisms remain obscure. Interleukin 18 (IL-18) is overproduced during chronic kidney diseases (CKD), but how IL-18 affects the biological behaviour of TEC is not clear. The aim of the present study is to reveal the role of IL-18 in renal TIF. Methods: The expressions of IL-18 and IL-18 receptor in TEC were detected by immunohistochemical staining in vivo and by reverse transcriptase polymerase chain reaction (RT-PCR) in vitro. TEC line (HK-2 cells) were incubated without or with IL-18. Cell proliferation and cell cycle were evaluated by methyl thiazolyl tetrazolium assay and flow cytometric analysis, respectively. Cell apoptosis was assessed by Hoechst 33258 staining. Expression of ,-smooth muscle actin was evaluated by RT-PCR, immunocytochemical staining and flow cytometric analysis, respectively. Type I collagen, fibronectin, MCP-1 and RANTES in cultured supernatants were measured by enzyme-linked immunosorbent assay. Results: IL-18 expression in TEC increased significantly in CKD state. IL-18 receptor was constitutively expressed in normal proximal TEC, and its expression increased strongly in CKD state. Proliferation and cell cycle of HK-2 cells were not affected by IL-18. Cell apoptosis, ,-smooth muscle actin expression, type I collagen and fibronectin production as well as MCP-1 secretion were promoted by IL-18 in dosage- and/or time-dependent manners, but RANTES secretion was not affected. Conclusion: IL-18 may play a crucial role in the process of TIF by promoting TEC injury and activation, and could be a target of the therapeutic approaches against TIF. [source] Role of heat shock protein 47 on tubulointerstitium in experimental radiation nephropathyPATHOLOGY INTERNATIONAL, Issue 5-6 2002Diange Liu The molecular mechanisms of fibrosis in radiation nephropathy have received scant attention. Heat shock protein 47 (HSP47), a collagen-binding stress protein, helps in the intracellular processing of procollagen molecules during collagen synthesis. We investigated the role of HSP47 in the progression of radiation nephropathy using experimental radiation nephropathy. Experimental rat groups were as follows: (i) group I, sham operated (n = 12); (ii) group II, single doses of irradiation, either 7, 15 or 25 Gy to left kidney (n = 60); and (iii) group III, a similar irradiation procedure as group II after right nephrectomy (n = 60). The rats were followed up until 9 months after renal exposure to radiation. Renal dysfunction (as determined by serum creatinine and blood urea nitrogen) and hypertension were noted in group III rats, along with inflammatory cell infiltration and interstitial fibrosis (as determined by increased deposition of collagens). Compared to control rat kidneys, an increased expression of HSP47 was noted in kidneys obtained from irradiated rats. By double immunostaining, HSP47-expressing cells were identified as ,-smooth muscle actin-positive myofibroblasts and vimentin-positive tubular epithelial cells. Increased expression of HSP47 was closely associated with increased deposition of collagens in the widened interstitium of irradiated rats. Overexpression of HSP47 by phenotypically altered tubulointerstitial cells might play a role in excessive assembly/synthesis of collagens and could contribute to tubulointerstitial fibrosis in radiation nephropathy. [source] Nox-2 Is a Modulator of Fibrogenesis in Kidney AllograftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009A. Djamali We studied the role of classical phagocytic NADPH oxidase (Nox) in the pathogenesis of kidney allograft tubulointerstitial fibrosis. Immunofluorescence studies showed that Nox-2 and p22phox (electron transfer subunits of Nox) colocalized in the tubulointerstitium of human kidney allografts. Tubular Nox-2 also colocalized with ,-SMA in areas of injury, suggestive of epithelial-to-mesenchymal transition (EMT). Interstitial macrophages (CD68+) and myofibroblasts (,-SMA+) expressed Nox-2 while graft infiltrating T cells (CD3+) and mature fibroblasts (S100A4+) were Nox-2,. These results were confirmed in the Fisher-to-Lewis rat kidney transplant model. Areas of tubulitis were associated with Nox-2 and ,-SMA, suggestive of EMT. Immunoblot analyses showed that Nox-2 upregulation was associated with oxidative stress (nitrotyrosine) and fibrogenesis (,-SMA and phospho-Smad2) at 3 weeks and 6 months. Allografts treated with Nox inhibitors (DPI or apocynin) for 1 week showed reduced fibronectin and phospho-Smad2 and increased E-cadherin levels. Cyclosporine A, TGF-,1 and angiotensin II increased Nox-2 mRNA levels 2- to 7-fold in vitro (NRK52E cells). Treatment with specific Nox inhibitors (DPI or apocynin) prevented the downregulation of E-cadherin and upregulation of fibronectin transcripts. In aggregate, these studies suggest that Nox-2 is involved in the pathogenesis of allograft tubulointerstitial fibrosis via activation transcription factor Smad2, EMT and myofibroblasts. [source] Detection of Acute Tubulointerstitial Rejection by Proteomic Analysis of Urinary Samples in Renal Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2005Stefan Wittke This study investigates proteomic analysis of urinary samples as a non-invasive method to detect acute rejection of renal allografts. Capillary electrophoresis coupled to mass spectrometry (CE-MS) was used to analyze urinary samples in 19 patients with different grades of subclinical or clinical acute rejection (BANFF Ia to IIb), 10 patients with urinary tract infection and 29 patients without evidence of rejection or infection. A distinct urinary polypeptide pattern identified 16 out of 17 cases of acute tubolointerstitial rejection, but was absent in two cases of vascular rejection. Urinary tract infection resulted in a different polypeptide pattern that allowed to differentiate between infection and acute rejection in all cases. Potentially confounding variables such as acute tubular lesions, tubular atrophy, tubulointerstitial fibrosis, calcineurin inhibitor toxicity, proteinuria, hematuria, allograft function and different immunosuppressive regimens did not interfere with test results. Blinded analysis of samples with and without rejection showed correct diagnosis by CE-MS in the majority of cases. Detection of acute rejection by CE-MS offers a promising non-invasive tool for the surveillance of renal allograft recipients. Further investigation is needed to establish polypeptide patterns in vascular rejection and to explore whether changes in the urinary proteome occur before the onset of histologically discernible rejection. [source] Pirfenidone Treatment Decreases Transforming Growth Factor-,1 and Matrix Proteins and Ameliorates Fibrosis in Chronic Cyclosporine NephrotoxicityAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2002Fuad S. Shihab Chronic cyclosporine (CsA) nephrotoxicity is characterized by tubulointerstitial fibrosis. Pirfenidone (PFD) is a novel antifibrotic compound that was shown to prevent and even reverse fibrosis. The mechanism of action of PFD is unclear but involves inhibition of transforming growth factor-, (TGF-,). Salt-depleted rats were administered CsA, CsA + PFD, vehicle (VH) or VH + PFD and sacrificed at 28 days. Physiologic and histologic changes were studied in addition to TGF-,1, plasminogen activator inhibitor-1 (PAI-1) and biglycan mRNA expressions by Northern blot. TGF-,1 immunohistochemistry was also performed. Treatment with PFD ameliorated CsA-induced fibrosis by about 50% (p <,0.05). CsA-induced decrease in creatinine clearance improved with PFD but the difference was not significant. TGF-,1, PAI-1 and biglycan mRNA expressions increased with CsA (p <,0.05 vs. VH) but strikingly improved with PFD treatment (p <,0.05 vs. CsA), which brought the levels down to VH levels. PFD treatment also decreased TGF-,1 protein expression by 80%. These results demonstrate that PFD can attenuate renal fibrosis in this model. PFD was associated with a decrease in TGF-,1 expression, which, in turn, was associated with a decrease in matrix deposition. These experiments suggest that PFD can be clinically useful for preventing chronic CsA nephrotoxicity and may prove to be helpful in other progressive renal diseases. [source] | ||||||||||