ABSTRACT
Hypoxia has been considered to be a significant microenvironmental factor in promoting renal fibrosis, which causes progressive kidney disease and renal allograft failure. Previous studies have demonstrated versatile functions of miR155 in hypoxia and fibrosis of the lung and liver. However, it is unclear whether miR155 is able to regulate renal fibrosis and what the detailed mechanisms of this may be. In the current study, we focused on the interaction of miR155/hypoxiainducible factor 1 alpha (HIF1α) and the effects of miR155 on fibrosis in hypoxic HK2 cells. Analysis of the expression of miR155 and fibrosisassociated cytokines revealed upregulated miR155, increased transforming growth factor beta 1 (TGFß1) and alphasmooth muscle actin, and decreased Ecadherin in hypoxic HK2 cells. Further study demonstrated that miR155 played a positive role in regulating HIF1α and vice versa. Moreover, the data illustrated the synergistic effects of upregulated miR155 on fibrosis by gainoffunction and lossoffunction methods in hypoxic HK2 cells. Notably, the results also revealed that miR155 had the ability to modulate TGFß1 and the process of epithelialmesenchymal transition (EMT). In conclusion, this study not only demonstrated that hypoxiainduced miR155 was a profibrotic cytokine which was positively regulated by HIF1α, but also revealed that miR155 promoted the fibrosis of proximal tubule cells by regulating both TGFß1 and the process of EMT under hypoxia.
Subject(s)
Cell Hypoxia , MicroRNAs/metabolism , Actins/metabolism , Cadherins/metabolism , Cell Line , Epithelial-Mesenchymal Transition , Fibrosis , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Kidney Tubules, Proximal/cytology , Kidney Tubules, Proximal/metabolism , MicroRNAs/antagonists & inhibitors , Oligonucleotides, Antisense/metabolism , Transforming Growth Factor beta1/metabolism , Up-RegulationABSTRACT
OBJECTIVE: To explore the expression of Glycogen synthase kinase 3 beta (GSK-3ß) in renal allograft tissue and its significance in the pathogenesis of chronic allograft dysfunction. METHODS: Renal allograft biopsy was performed in all of the renal allograft recipients with proteinuria or increased serum creatinine level who came into our hospital from January 2007 to December 2009. Among them 28 cases was diagnosed as chronic allograft dysfunction based on pahtological observation, including 21 males with a mean age of 45 ± 10 years old and 7 females with a mean age of 42 ± 9 years old. The time from kidney transplantation to biopsy were 1-9 (3.5) years. Their serum creatinine level were 206 ± 122 umol/L. Immunohistochemical assay and computer-assisted genuine color image analysis system (imagepro-plus 6.0) were used to detect the expression of GSK-3ß in the renal allografts of 28 cases of recipients with chronic allograft dysfunction. Mean area and mean integrated optical density of GSK-3ß expression were calculated. The relationship between expression level of GSK-3ß and either the grade of inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft was analyzed. Five specimens of healthy renal tissue were used as controls. RESULTS: The expression level of the GSK-3ß was significantly increased in the renal allograft tissue of recipients with chronic allograft dysfunction, compared to normal renal tissues, and GSK-3ß expression became stronger along with the increasing of the grade of either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft tissue. CONCLUSION: There might be a positive correlation between either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy and high GSK-3ß expression in renal allograft tissue. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/9924478946162998.
Subject(s)
Delayed Graft Function/metabolism , Glycogen Synthase Kinase 3/biosynthesis , Kidney Transplantation/adverse effects , Adult , Atrophy/pathology , Delayed Graft Function/pathology , Female , Fibrosis/pathology , Glycogen Synthase Kinase 3 beta , Humans , Immunohistochemistry , Inflammation/pathology , Male , Middle Aged , Transplantation, HomologousABSTRACT
OBJECTIVE: To investigate the expressions of matrix metalloprotein-2 (MMP-2) and tissue inhibitor of metallopeptidase inhibitor-1 (TIMP-1) in the renal allografts of patients with chronic active antibody-mediated rejection (ABMR), and explore their role in the pathogenesis of ABMR. METHODS: Immunohistochemistry and computer-assisted image analysis were used to detect the expression of MMP-2 and TIMP-1 in the renal allografts of 46 patients with interstitial fibrosis and tubular atrophy (IF/TA), with 15 normal renal tissue specimens as the control. The association of MMP-2 and TIMP-1 with the pathological grade of IF/TA in ABMR was analyzed. RESULTS: The expressions of MMP-2 and TIMP-1 significantly increased in the renal tissues of the patients as compared with the normal renal tissues (P<0.05). MMP-2 expression tended to decrease, while TIMP-1 and serum creatinine increased with the pathological grades of IF/TA (P<0.05). In IF/TA group, the expression of TIMP-1 was positively correlated to serum creatinine level (r=0.718, P=0.00<0.05). CONCLUSION: Abnormal expressions of MMP-2 and TIMP-1 can promote the development of renal fibrosis in chronic ABMR.
Subject(s)
Graft Rejection/immunology , Kidney Transplantation , Kidney/metabolism , Matrix Metalloproteinase 2/metabolism , Tissue Inhibitor of Metalloproteinase-1/metabolism , Adult , Antibody Formation , Complement C4b/metabolism , Female , Fibrosis/etiology , Humans , Kidney Diseases/pathology , Kidney Transplantation/adverse effects , Kidney Transplantation/immunology , Male , Matrix Metalloproteinase 2/genetics , Middle Aged , Peptide Fragments/metabolism , Tissue Inhibitor of Metalloproteinase-1/geneticsABSTRACT
OBJECTIVE: To study the protection of Gan by using deoxyschizandrin (Wuzhi Capsule, WC) in the renal transplantation recipients while increasing the blood concentration of tacrolimus (Tac). METHODS: Seventy-three renal transplant recipients were randomly assigned to two groups, i.e., 35 in the WC group and 38 in the control group. All patients received Tac + MMF + Pred triple immunosuppressive therapy. WC was additionally given to patients in the WC group. One year was taken as one therapeutic course. Changes of the blood concentration of Tac were detected one week, 1, 3, 6, and 12 months after medication in the two groups using microparticle enzyme immune assay (MEIA). Meanwhile, the liver and kidney functions, and the blood glucose were tested. RESULTS: One week after the application of WC, the blood Tac concentration increased 67.2% averagely. During the 1 -12 months of WC treatment, the Tac dosage was significantly lower in the WC group than in the control group (P<0.01). There was no significant difference in the liver and renal functions, or the blood glucose levels between the two groups (P>0.05). CONCLUSION: WC could significantly increase the blood Tac concentration of renal transplant recipients, reduce their Tac dosages, with no obvious adverse reaction.
Subject(s)
Drugs, Chinese Herbal/therapeutic use , Kidney Transplantation , Adolescent , Adult , Drugs, Chinese Herbal/pharmacology , Female , Graft Survival , Humans , Male , Middle Aged , Postoperative Period , Tacrolimus/blood , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: To investigate the expression of integrin-linked kinase (ILK) and collagen IV in renal allografts with interstitial fibrosis and tubular atrophy (IF/TA) in kidney transplant recipients, and explore its relationship with transforming growth factor-beta(1) (TGF-beta(1)) expression and the pathogenesis of IF/TA. METHODS: Immunohistochemical assay and computer-assisted genuine colored image analysis system were used to detect the expression of ILK, TGF-beta(1) and collagen IV in the renal allografts with IF/TA. The association between TGF-beta(1), collagen IV and ILK, as well as the relationship between their expressions and the pathological class of IF/TA, was analyzed. 10 specimens of healthy renal tissue were used as controls. RESULTS: The expression levels of ILK, TGF-beta(1) and collagen IV in renal allografts were significantly higher, compared to normal renal tissues (P<0.001), and the expressions tended to increase along with the increase of pathological class of IF/TA. In IF/TA group, the expression of ILK was positively correlated with the expression of TGF-beta(1) and collagen IV (r=0.976 and r=0.912, respectively; P<0.001 for both). CONCLUSION: It is suggested that by the data that ILK might mediate the mechanism through which TGF-beta(1) promote the abnormal deposition of ECM in renal allografts with IF/TA. ILK might play an important role in the progression of the interstitial fibrosis and tubular atrophy of human renal allografts and the development of chronic renal allograft dysfunction.
Subject(s)
Collagen Type IV/metabolism , Fibrosis/physiopathology , Gene Expression Regulation , Kidney Transplantation , Kidney Tubules/physiopathology , Nephritis, Interstitial/physiopathology , Protein Serine-Threonine Kinases/metabolism , Humans , Kidney/enzymology , Transplantation, HomologousABSTRACT
OBJECTIVE: To investigate the risk factors of insulin resistance (IR) and the role of IR and metabolic syndrome in the pathogenesis of chronic allograft nephropathy (CAN). METHODS: One hundred and twenty-seven kidney transplant recipients with normal renal function and no proteinuria at the 6th month after transplantation, and without the experience of acute rejection, calcinurine intoxication and severe infection, were involved in the study. Their primary disease of ESRF was chronic glomerulonephritis but not diabetes mellitus and hypertension. Half year and one year after transplantation, blood and urine biochemical determinations and physical examination were performed in the recipients, and HOMA calculated. 200 ordinary community residents were randomized selected as controls. RESULT: The incidence of MS in the recipients was significantly higher than controls. The incidences of obesity and overweight between recipients and controls were no significant difference. While the insulin resistance level and urine albumin level, and the incidence of MS and microalbuminuria (MAU) were significantly higher in recipients with obesity or overweight than that in recipients without obesity or overweight. The insulin resistance level in tacrolimus-treated recipients was markedly higher than CsA-treated recipients, and there was a positive correlation between the blood concentration of tacrolimus and insulin resistance level. MAU positive recipients had higher insulin resistance levels than the recipients without MAU. The recipients with metabolic syndrome had higher insulin resistance levels compared to recipients without metabolic syndrome, and higher insulin resistance levels existed in recipients with hypertriglyceridemia or hypercholesterolemia, hypertension. CONCLUSION: It is shown in the study that obesity or overweight, tacrolimus (especially when its blood concentration was high) were risk factors resulting in insulin resistance in kidney transplant recipients. It is suggested in the study that insulin resistance often accompanied with hypertriglyceridemia, hypercholesterolemia and hypertension in kidney transplant recipients might be involved in the pathogenesis of the pathogenesis of CAN.