Novel mechanisms driving renal tubulointerstitial fibrosis / 中国临床药理学与治疗学

Renal fibrosis, especially tubulointerstitial fibrosis, is the most common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Several adaptive reactions occur in renal tubular epithelial cells after chronic injury, such as changes in glycolipid metabolism, unfolded protein response, autophagy and senescence, epithelial-to-mesenchymal transition and G2/M cell cycle arrest. Maladaptive repair mechanisms can induce tubulointerstitial fibrosis. This article will discuss the molecular mechanism of these adaptive responses of renal tubular epithelial cells driving renal tubulointerstitial fibrosis, and provide a basis for exploring new drug targets for renal tubulointerstitial fibrosis.

Nephrotic syndrome in the elderly: epidemiological aspects, clinical data, and renal biopsy findings

Nephrotic syndrome is the most common clinical presentation of glomerular disease in elderly patients, and renal biopsy is an important diagnostic resource. The aim of this study was to describe nephrotic syndrome among elderly patients in Brazil, focusing on tubulointerstitial and vascular involvement. This was a retrospective study of patients over 65 years of age with nephrotic syndrome who underwent renal biopsy between January 2012 and December 2019. Of the 123 renal biopsies that occurred during the study period, 44 (35.8%) were performed for the investigation of nephrotic syndrome. Among those 44 cases, the main etiologies were membranous nephropathy in 13 cases (29.5%), amyloidosis in ten (22.7%), non-collapsing focal segmental glomerulosclerosis (FSGS) in four (9.1%), and collapsing FSGS in four (9.1%). Patients with minimal change disease (MCD) had the lowest degree of interstitial fibrosis compared with the other glomerulopathies, and histological signs of acute tubular necrosis (ATN) were less common among those with amyloidosis than among those with membranous nephropathy, FSGS, or MCD (P=0.0077). Of the patients with ATN, the frequency of acute kidney injury (AKI) was highest in those with MCD (P<0.001). All patients had some degree of vascular involvement, regardless of the type of glomerulopathy. In conclusion, the second most common cause of nephrotic syndrome in this population was amyloidosis, and acute interstitial tubule involvement was more marked in MCD. Vascular involvement is something that cannot be dissociated from the age of the patient and is not only due to the underlying glomerulopathy.

Blockage of TGF-β1-induced epithelial-to- mesenchymal transition by oxymatrine prevents renal interstitial fibrosis

Abstract Most chronic kidney disease inevitably progress to renal fibrosis. Tubular epithelial- to-mesenchymal transition (EMT) is recognized to play major roles in renal fibrosis. Oxymatrine (OM) is a major alkaloid component found in a Chinese herb Sophora roots and has many effects. The aim is to investigate the effect of OM on renal tubular EMT and elucidate its mechanism. Mice underwent unilateral ureteral obstruction (UUO) followed by intraperitoneal injection of OM (120 mg/kg) or control vehicle. Human kidney proximal tubular cell line (HK-2) was used and EMT was induced with 5 ng/mL of transforming growth factor-β1 (TGF-β1). In vivo, renal tubulointerstitial fibrosis was induced and E-cadherin was down-regulated, while the expressions of fibronectin (FN), α-smooth muscle actin (α-SMA), TGF-β1 and its type I receptor (TGF-βRI) were up-regulated in UUO mice. In contrast, OM significantly ameliorated renal fibrotic lesions and attenuated the expressions of FN, α-SMA, TGF-β1 and TGF-βRI, but increased E-cadherin in the obstructed kidneys. In vitro, OM abolished TGF-β1-mediated E-cadherin suppression and FN, α-SMA and TGF-βRI induction in HK-2 cells in a dose-dependent manner. These observations strongly suggest that the renal protective effects of OM could be mediated by prevention of EMT and manifested as suppression of TGF-β1 and TGF-βRI expressions.

The expression and significance of N-myc downstream regulated gene-2 in rat kidney after ureteral obstruction / 国际儿科学杂志

Objective To investigate the expression of N-myc downstream regulated gene-2 (NDRG2) on renal fibrosis in unilateral ureteral obstruction(UUO) rat model and the mechanism of renal fibrosis.Methods Forty-eight male Wistar rats (120-150g)were randomly divided into two groups:the sham-operation group (n =24)underwent the left ureteral dissection,the UUO group (n =24)underwent the left ureteral ligation.At the 3,7,14,21day after the operation,6 rats from each of the group were sacrificed and the obstructive kidneys were collected.The histopathological changes were observed through HE and Masson staining.E-cadherin and α-SMA were detected by Western blot and immunohistochemistry.NDRG2 were detected by Western blot,immunohistochemistry and real-time PCR.Results There is not diffenrence in the sham group at anytime.Compared with the sham-group,the fibrosis was obvious in UUO group.The protein of E-cadherin decreased(P ＜ 0.05) and α-SMA increased(P ＜0.05).The expression of NDRG2 in UUO group was lower than that in the sham group.The OD of immunohistochemistry was detected by ImagePro Plus 6.0.OD of NDRG2 was the lowest[(14.33 ± 2.45) x 10-3] in 21d group.The western blot showed that the ratio of NDRG2 to β-actin was the lowest(0.03 ± 0.01) in 21d group.The mRNA of NDRG2 decreased obverously in UUO group (P ＜ 0.05).Conclusion NDRG2 decreases in UUO group and NDRG2 might be involved in the pathologic process of renal fibrosis.

Lobeglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

BACKGROUND: Renal tubulointerstitial fibrosis is a common feature of the final stage of nearly all cause types of chronic kidney disease. Although classic peroxisome proliferator-activated receptor γ (PPARγ) agonists have a protective effect on diabetic nephropathy, much less is known about their direct effects in renal fibrosis. This study aimed to investigate possible beneficial effects of lobeglitazone, a novel PPARγ agonist, on renal fibrosis in mice. METHODS: We examined the effects of lobeglitazone on renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) induced renal fibrosis mice. We further defined the role of lobeglitazone on transforming growth factor (TGF)-signaling pathways in renal tubulointerstitial fibrosis through in vivo and in vitro study. RESULTS: Through hematoxylin/eosin and sirius red staining, we observed that lobeglitazone effectively attenuates UUO-induced renal atrophy and fibrosis. Immunohistochemical analysis in conjunction with quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that lobeglitazone treatment inhibited UUO-induced upregulation of renal Smad-3 phosphorylation, α-smooth muscle actin, plasminogen activator inhibitor 1, and type 1 collagen. In vitro experiments with rat mesangial cells and NRK-49F renal fibroblast cells suggested that the effects of lobeglitazone on UUO-induced renal fibrosis are mediated by inhibition of the TGF-β/Smad signaling pathway. CONCLUSION: The present study demonstrates that lobeglitazone has a protective effect on UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of non-diabetic origin renal disease.

Effects of exogenous hydrogen sulfide on the expressions of angiotensinⅡand proliferating cell nuclear an-tigen of tubulointerstitial fibrosis in rats with unilateral ureteral obstruction / 医学研究生学报

Objective Tubulointerstitial fibrosis(TIF) is the most important marker reflecting the degree of renal function decline and prognosis and hydrogen sulfide ( H2 S) is crucial in maintaining normal renal function and many diseases of renal injury. The aim of the article was to investigate the effects of exogenous H2 S on the expressions of angiotensinⅡ ( AngⅡ) , proliferating cell nuclear antigen (PCNA) and transforming growth factor beta-1 (TGF-β1) in rats with unilateral ureteral obstruction (UUO). Methods TIF rat model was built with UUO. Ninety-six SD rats were randomly divided into four groups:sham operation group, modelgroup, UUO+low-dose NaHS treatment group ( low dose group) and UUO+high-dose NaHS treatment group ( high dose group) ( n=24, respectively) . Rats in model group were treated with left-side ureteral obstruction and ureteral separation without obstruction was done in sham operation group. UUO rats in two treatment groups were injected intraperitoneally with two different doses of sodium hydrosulfide (NaHS, donor of endogenous H2 S), respectively. HE and Massonstaining and immunohistochemical staining were performed at the 7 d, 14 d and 21 d, respectively. Results In sham operation group, the expressions of AngⅡ, PCNA, and TGF-β1 were found in microamount in tubulointerstitium at each time points. Compared with sham operation group, the expressions of AngⅡ, PCNA and TGF-β1 in model group increased( P<0.01) . While in comparison to model group, the expressions of AngⅡ, PCNA and TGF-β1 decreased in low dose group and high dose group, but no significant differ-ence was found between low dose group and high dose group. Conclusion Exogenous H2 S supplementation can attenuate TIF partly via downregulating the expressions of AngⅡ, PCNA and TGF-β1 .

AEG-1 participates in high glucose-induced activation of Rho kinase and epithelial-mesenchymal transition in proximal tubular epithelial cells

Objective: To prove whether astrocyte elevated gene-1 (AEG-1) plays a role in high glucose-stimulated Rho kinase activation and epithelial-mesenchymal transition (EMT) in human renal tubular epithelial (HK-2) cells. Methods: The protein levels of AEG-1, alpha-smooth muscle actin, E-cadherin and MYPT1 were determined by Western blot. Results: AEG-1 protein level was upregulated in HK-2 cells stimulated with high glucose. AEG-1 siRNA downregulated Rho kinase protein expression and blocked high glucose-induced EMT. Conclusions: Our results show that AEG-1 acts a key role in high glucose-induced activation of Rho kinase and EMT in HK-2 cells.

AEG-1 participates in high glucose-induced activation of Rho kinase and epithelial-mesenchymal transition in proximal tubular epithelial cells

OBJECTIVE@#To prove whether astrocyte elevated gene-1 (AEG-1) plays a role in high glucose-stimulated Rho kinase activation and epithelial-mesenchymal transition (EMT) in human renal tubular epithelial (HK-2) cells.@*METHODS@#The protein levels of AEG-1, alpha-smooth muscle actin, E-cadherin and MYPT1 were determined by Western blot.@*RESULTS@#AEG-1 protein level was upregulated in HK-2 cells stimulated with high glucose. AEG-1 siRNA downregulated Rho kinase protein expression and blocked high glucose-induced EMT.@*CONCLUSIONS@#Our results show that AEG-1 acts a key role in high glucose-induced activation of Rho kinase and EMT in HK-2 cells.

Yishen Jiangzhuo Granules affect tubulointerstitial fibrosis via a mitochondrion-mediated apoptotic pathway / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate the effect of Yishen Jiangzhuo Granules, YSJZG) on mitochondrial injury and regeneration and renal tubular epithelial cell apoptosis in chronic renal failure (CRF) rats and explore its mechanism from molecular pathology, gene, protein levels, and relative pathway.</p><p><b>METHODS</b>The CRF rat model was established using 5/6 nephrectomy. Sixty rats were randomly divided into six groups: sham-operation group, model (CRF) group, Niaoduqing Granules-treated group [5 g/(kg.day)], low-, moderate-, and high-dose [L-YSJZG, M-YSJZG, H-YSJZG at 3, 6, and 9 g/(kg day)] YSJZG-treated group (n=10 each). The levels of serum creatinine (Scr), blood urea nitrogen (BUN), and 24-h urine protein were assessed after 10 weeks of treatment. The tubulointerstitial injury and collagen deposition were evaluated using periodic acid-schiff stain and Masson staining. Renal tubular epithelial cell apoptosis was assessed using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay, mitochondrial injury was observed using an electron microscope, and superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) levels were assessed using chromometry. Transforming growth factor-β1 (TGF-β1) expression was assessed using immunohistochemistry. The expressions of Bax, Bcl-2, peroxisome proliferator-activated receptor γ coactivator- 1α (PGC-1α), mitochondrial transcription factor A (Tfam), mitogen-activated protein kinases (MAPK) phosphorylation were evaluated by Western blot.</p><p><b>RESULTS</b>YSJZG decreased the 24-h urine protein, BUN, Scr, remnant kidney weight-to-body weight ratio, renal tubular injury, deposition of collagen, and the apoptosis of renal tubular epithelial cells in a dose-dependent manner. YSJZG dose-dependently restored the number and structure of mitochondria and the expression of Tfam and PCG-1α, up-regulated the expression of Bcl-2, and inhibited the expression of Bax. YSJZG also dose-dependently inhibited TGF-β1 expression, increased SOD and GSH activity, decreased the MDA level, and inhibited p38MAPK and pERK1/2 phosphorylation (all P<0.01).</p><p><b>CONCLUSION</b>YSJZG improved the renal function in rats with CRF and inhibited the progression of tubulointerstitial fibrosis by dose-dependently alleviating mitochondrial injury, restoring the expression of Tfam and PCG-1α, and inhibiting renal tubular epithelial cell apoptosis through inhibiting activation of reactive oxygen species-MAPK signaling.</p>

Influence of paricalcitol on renal tubulointerstitial fibrosis in diabetic ne-phropathy / 中国病理生理杂志

[ ABSTRACT] AIM:To investigate the effect of paricalcitol ( P) on renal tubulointerstitial fibrosis and the under-lying mechanisms in diabetic nephropathy ( DN) .METHODS:DN rat model was induced by a single intraperitoneal in-jection of streptozotocin after fasting.The animals were randomly divided into 2 groups: the DN rats in paricalcitol-inter-vened group ( group P) were injected intraperitoneally with paricalcitol dissolved in propylene glycol after the day when the model was induced successfully at a dose of 0.4μg/kg (3 times a week);the DN rats in DN group ( group D) were given isopyknic propylene glycol.Normal control group ( group C) was also set up.The samples of blood, urine and renal tissue were collected after intervention of paricalcitol for 12 weeks.The biochemical indexes were measured.The renal tissues were used for pathologic observation and determining the expression of transforming growth factor-β1 (TGF-β1), Wnt-4,β-catenin and Klotho by immunohistochemistry and Western blotting.In addition, the correlation among the above indexes was analyzed.RESULTS:(1) Scr, BUN and 24 h urine protein increased significantly in group D compared with group C, while decreased in group P compared with group D ( P<0.05 ) .( 2 ) The area of renal tubulointerstitial fibrosis in-creased in group D compared with group C, while decreased in group P compared with group D (P<0.05).(3) The ex-pression of Klotho decreased, while the expression of TGF-β1, Wnt-4 and β-catenin increased in group D compared with group C (P<0.05).Compared with group D, the expression of Klotho increased, while the expression of TGF-β1, Wnt-4 andβ-catenin decreased in group P (P<0.05).(4) The expression of Klotho was negatively correlated with the fibrosis area, TGF-β1, Wnt-4 andβ-catenin (P<0.05).CONCLUSION:Paricalcitol inhibits renal tubulointerstitial fibrosis in DN by promoting the expression of renal Klotho, and inhibiting Wnt/β-catenin signaling pathway activation and TGF-β1 synthesis.

Fracción de excreción de magnesio y estado del túbulo-intersticio en pacientes nefróticos / Fractional excretion of magnesium and status of tubulointerstitium in nephrotic patients

INTRODUCCIÓN: la fracción de excreción de los electrólitos puede constituir un marcador temprano de daño renal en las glomerulopatías. OBJETIVO: identificar la posible relación existente entre variables clínicas, fracción de excreción de magnesio y estado del túbulo-intersticio, en pacientes con proteinuria nefrótica a los que se les realizó biopsia renal en el Instituto de Nefrología entre abril de 2012 y junio de 2013. MÉTODOS: se realizó un estudio observacional analítico, transversal, en el que se excluyeron los pacientes con factores que modificaran la fracción de excreción de magnesio. A los 40 pacientes incluidos en el estudio se les recogieron datos antropométricos, demográficos y clínicos, se les midió la fracción de excreción de magnesio, se les practicó biopsia renal y se les cuantificó el porcentaje de fibrosis con el programa Image J. La información fue procesada mediante el paquete estadístico SPSS 15.0. Se utilizó la técnica estadística de análisis de distribución de frecuencias, en las variables cuantitativas se calcularon estadígrafos descriptivos. Fueron empleados los tests de Wilcoxon, de Kruskal Wallis y el coeficiente de correlación de Spearman's-rho, en las pruebas de hipótesis. RESULTADOS: se encontró correlación estadísticamente significativa de la fibrosis intersticial con la fracción de excreción de magnesio (rsp= 0,37, p= 0,02) y con la tasa de filtración glomerular (rsp= -0,56, p= 0,00). No fue encontrada asociación de la fracción de excreción de magnesio con el empleo de medicamentos, ni con el antecedente de hipertensión arterial. CONCLUSIÓN: la fibrosis intersticial se relaciona con la fracción de excreción de magnesio y con la tasa de filtración glomerular en pacientes con proteinuria nefrótica.

INTRODUCTION: fractional excretion of electrolytes can be used as an early marker of renal damage in glomerulopathies. OBJECTIVE: to identify the possible relationship between some clinical variables, the fractional excretion of magnesium and the tubulointerstitial status in patients with nephrotic proteinuria assisted at The National Institute of Nephrology from April 2012 to June 2013. METHODS: an observational analytical study was conducted. Patients with conditions that modify the fractional excretion of magnesium were excluded. 40 patients were included in this study at the Institute of Nephrology from April 2012 until June 2013, and their demographic, anthropometric and clinical data were collected; the fractional excretion of magnesium was measured as well. Renal biopsies were practiced to all patients and the percent of fibrosis was measured with the aid of image J program. Data were processed with Statistical package for Social Science (SPSS) version 15.0. The statistical technique of frequency distribution analysis was used; quantitative variables descriptive statistics were calculated. Wilcoxon tests, Kruskal Wallis and correlation coefficient Spearman's- rho were used in hypothesis tests. RESULTS: the percent of interstitial fibrosis was related to fractional excretion of magnesium (rsp= 0,37, p= 0,02) and glomerular filtration rate (rsp= -0,56, p= 0,00). No association of the fractional excretion of magnesium with the use of drugs or with history of hypertension was found. CONCLUSIONS: tubulointerstitial fibrosis is related to the fractional excretion of magnesium and glomerular filtration rate in patients with nephrotic proteinuria.

Expression of CNP/NPR-B axis and NPR-C/NEP elimination pathways in rats with unilateral ureteral obstruction / 临床儿科杂志

Objectives To study the expression features of C-type natriuretic peptide (CNP)/natriuretic peptide receptor-B (NPR-B) axis and two parallel elimination pathways, natriuretic peptide receptor-C (NPR-C) and neutral endopeptidase (NEP) in unilateral ureteral obstruction (UUO) rats. Methods CNP, NPR-B, NPR-C, NEP, Col-IV and type IV collagen (Col-IV) mRNA and proteins were determined by in situ hybridization, real-time PCR, immunohistochemistry and western blot in UUO rats at 24h, 72h, 1w, 2w, 3w, 1m, 2m and 3m. Results CNP expression tended to be higher immediately after ligation and de-clined along with the progression of disease, occurring predominantly in tubular epithelial cells. A high-level CNP may attribute to the elevated expression of NPR-B in the early phase of UUO. Conclusions NEP and NPR participate in the regulation of CNP expression in tubulointerstitial fibrosis. The gradual increased expression of NPR-C and NEP may cause the subsequent de-cline of CNP.

Changes of mobility of kidney tubular epithelial cells in the course of epithelial-mesenchymal transition / 中华实用儿科临床杂志

Objective To evaluate the dynamic changes of cell mobility of renal tubular epithelial cells in the course of epithelial-mesenchymal transition(EMT) and their effect on cell cycle.Methods NRK-52E cells were cultured in vitro and treated with 5 μg/L transforming growth factor(TGF)-β1 to induce EMT.The cell mobility was assessed by using Transwell chamber assay and flow cytometry (FCW) after being treated with TGF-β1 for 4 h,8 h,12 h,24 h and 48 h.The proliferative cell cycle of NRK-52E cells were evaluated by using the FCW.Results 1.EMT was successfully induced by TGF-β1.After being treated by TGF-β1 (5 μg/L),the morphological changes of NRK-52E cells were found with loose cell arrangement and elongated fusiform change in cells body.Meanwhile,after getting treated by TGF-β1,the expressions of E-cadherin protein(epithelial marker) of NRK-52E cells were significantly decreased with time-dependent (P ＜ 0.05),while the expressions of α-smooth musle actin (α-SMA) (mesenchymal cell marker)were significantly increased with time-dependent (P ＜ 0.05).2.The Transwell chamber assay showed that compared with the control group,the cell mobility in the group treated with TGF-β1 was significantly enhanced from 12 h after getting treated with TGF-β1 (P ＜ 0.01).3.The proliferative cell cycle of NRK-52E cells showed no significant difference after being treated with TGF-β1 (P ＞ 0.05).Conclusions The migration ability of the NRK-52E cells are increased incessantly in the course of EMT,which is induced by TGF-β1 without the influence of cell proliferation in vitro.

Validation of Tissue Microarrays for the Study of Immunosuppressive Agent-induced Nephrotoxicity / 대한이식학회지

BACKGROUND: Tissue microarray analysis (TMA) is a high-throughput method for histologic evaluation, immunohistochemistry, and in situ hybridization using paraffin embedded tissue. Despite its high efficiency as an experimental tool, TMA is limited because it only contains a very small tissue fragment from each case. Therefore, the purpose of this study was to evaluate the validity of TMA in a study of nephrotoxicity caused by immunosuppressants. METHODS: Male Sprague-Dawley rats were treated with vehicle (n=16), cyclosporine (n=23), and cyclosporine plus losartan (n=13) for a maximum of 7 weeks. After animal sacrifice, renal tissues were embedded in paraffin and processed into slides for microscopic examination using conventional methods and the TMA technique. Acute tubular injury, vascular hyaline change, and interstitial fibrosis were scored in both conventional and TMA slides. The number of interstitial macrophages was counted after ED-1 immunohistochemistry and the results also compared between conventional and TMA slides. RESULTS: The degree of acute tubular injury and interstitial fibrosis showed a significant agreement between conventional and TMA methods (kappa value, 0.79 and 1.00, respectively). The number of interstitial macrophages counted in conventional and TMA slides showed a significant correlation as well (r=0.934, P<0.001). However, the degree of vascular hyaline changes showed less agreement between conventional and TMA methods (kappa value, 0.40). CONCLUSIONS: TMA is a useful and reliable method for the study of nephrotoxicity induced by immunosuppressive agents. TMA also reflects the findings of conventional methods, especially for acute and chronic tubular and interstitial changes.

Progress in renal tubulointerstitial fibrosis / 国际儿科学杂志

Renal tubulointerstitial fibrosis is the final common pathway in end-stage renal disease.Whereas molecular mechanisms underlying fibrogenesis are still not completely understood.To know the latest pathogenesis and treatment methods is of important significance to prevent disease progression and save life.

Change of TGF-β receptor subtype expression in the kidney of rats with unilateral ureteral obstruction / 中华肾脏病杂志

ObjectiveTo investigate the influence of TGF-β receptor subtypes expression and their downstream signaling Smad proteins on rat renal interstitial fibrosis induced by unilateral ureteral obstruction(UUO).MethodsA total of 90 rats were randomly divided into three groups:normal control(CON),sham operation (SOR) and UUO group,and sacrificed 1,3,7,14 and 21 days after operation.Serum creatinine and urea nitrogen were detected to assess renal function.PAS and Masson staining were performed to observe histological damage in the kidneys.Quantitative RT-PCR was used to define expression of mRNA encoding TGF-β receptor subtypes and their downstream signaling Smad proteins in kidney tubular cells.Real-time PCR,Western blotting and immunofluorescence were used to monitor the time-related expression of the TGF-β receptor subtypes and their downstream signaling Smad proteins in kidney.ResultsCompared with the CON group,serum creatinine and urea nitrogen in UUO groups increased at day 3 after operation (P＜0.05) and reached their peak 21 days after operation (P＜0.01).Obvious inflammatory cell infiltration was observed in UUO group 3 days after operation,while renal tubular atrophy and renal interstitial fibrosis were observed in UUO group14 days after operation.The mRNA expressions of ALK-5,ALK-7 and TGF-βR Ⅱ increased significantly in UUO group 3 days after operation (all P＜0.05) and reached their peaks 14 days after operation (all P＜0.01).The mRNA expression of ALK-6 decreased significantly in UUO group 3 days after operation(P＜0.05) and reached its lowest level 14 days after operation (P＜0.01).The changes in the protein level of those receptors were consistent with their mRNA expressions.The protein expressions of Smad2/3 and p-Smad2/3 increased significantly in UUO group at day 3(all P＜0.05) and reached their peak at day 14 after operation(all P＜0.01).ConclusionExpressions of TGF-β receptor subtypes ALK-5,ALK-6,ALK-7,TGF-βR Ⅱ and their downstream signaling Smad2 and Smad3 proteins may influence the progress of renal interstitial fibrosis,tubular atrophy and inflammatory cell infiltration in UUO model rats.

Effects and Mechanism of Irbesartan on Tubulointerstitial fibrosis in 5/6 Nephrectomized Rats / 华中科技大学学报（医学）（英德文版）

Tubulointerstitial fibrosis(TIF)is a common pathological feature of end-stage kidney disease.Previous studies showed that upregulation of TGFβ1 notably contributed to the chronic renal injury and irbesartan halted the development of TIF in rats with 5/6 renal mass reduction.This study was to investigate the effects of irbesartan on chronic TIF and the mechanism involved TGFβ1 in the rodent model of chronic renal failure involving 5/6 nephrectomy.The results showed that irbesartan significantly attenuated the rise in blood pressure and tubulointerstitial injury observed in this model.Masson staining of the renal tissue revealed that there appeared severe renal tubule atrophy and fibrosis in operation group,but the lesion was attenuated mostly in irbesartan-treated group.Immunohistochemistry showed that irbesartan treatment apparently decreased the protein expression of TGFβ1 which was up-regulated in operation groups.Western blot showed that irbesartan treatment down-regulated the expression of TGFβ1,phosphorylated smad2(p-smad2),AT1R and phosphorylated p38(p-p38)MAPK,but significantly up-regulated the protein expression of smad6 as compared with operation group.These findings suggest that irbesartan attenuates hypertension and reduces the development of TIF in rats with 5/6 renal mass reduction via changes in the expression of these proteins at least including smad6,TGF-β1,p-smad2,AT1 and p-p38 MAPK.

Progress of function and mechanism of tissue transglutaminase in the process of tubulointerstitial fibrosis / 国际儿科学杂志

Tubulointerstitial fibrosis is the final common pathway of most progressive renal diseases, and also is the pathological basis that leading to chronic renal failure. In recent years, the biological effect of tissue transglutaminase in the progressive tubulointerstitium fibrosis attracts more and more attention. Tissue transglutaminase belongs to a group of calcium-dependent mammalian enzymes that have the capacity to irreversibly cross-link proteins through the formation of e (γ-glutamyl)lysine bonds, and lead to the excessive deposition of extracellular matrix, then functions markedly in the tubulointerstitial fibrosis.

The critical role of tubulointerstitium in renal disease progression.

Background: Recent works have demonstrated that, regardless of the primary causes, tubulointerstitial (TI) fibrosis is the major cause of progression of renal failure. Objective: To summarize the mechanisms of progression and regression of TI damage. Results: Experimental studies have shown that there are three common processes of progressive TI damage: injury, inflammation, and fibrosis. Renin angiotensin system (RAS) blocking agents could substantially decrease these lesions. Conclusion: The fulcrum of the balance between progression and regression of TI fibrosis remains to be elucidated but would be related to the activation of RAS.

Therapeutic strategy towards renal restoration in chronic kidney disease.

Background: The population with end-stage renal disease is increasing. This continued growth is related to: i) diagnostic failure in screening for early chronic kidney disease (CKD) associated with tubulointerstitial fibrosis (TIF), ii) failure in preventing renal disease progression due to lack of understanding of the precise determinants that induce TIF, and iii) delayed treatment which simply slows renal disease progression, but is unable to restore renal function. Objective: To review therapeutic strategy to restore renal function in CKD stressing fractional excretion of magnesium (FE Mg) as a sensitive biomarker for screening early CKD associated with TIF. Results: There is much evidence to support the crucial role of renal microvascular disease as the determinant of TIF and disease progression. A unique pattern of hemodynamic maladjustment is characterized by a preferential constriction of the efferent arteriole that induces peritubular capillary flow reduction in CKDs. Conclusion: The present information leads to a therapeutic strategy to restore renal function in early CKD patients.