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Background/Aims: We aimed to explore the associations between clinical parameters and long-term allograft outcomes in transplant glomerulopathy (TG) in a large retrospective cohort with long follow-up. Methods: Clinical and laboratory data at biopsy from 180 cases of TG with an estimated glomerular filtration rate (eGFR)> 15ml/min/1.73m2 from January 2004 to December 2016 at our center were retrospectively analyzed. The main outcome of this study was initiation of replacement therapy or an eGFR declined to < 15 ml/min/1.73m2. Results: During a median follow-up of 5 years (interquartile range 2.6-8.2 years), 117 cases (65.0%) achieved the combined event. Kaplan-Meier method yielded the 1-year and 5-year cumulative renal allograft survival rates after a histopathologic diagnosis of TG were 84% (95% confidence interval [CI] 81-87%) and 33% (95% CI 27–39%) respectively. In univariate analysis, allograft outcome differed significantly by eGFR, proteinuria, blood hemoglobin level, urinary retinol-binding protein (urRBP) and urinary N-acetyl-β-D-glucosaminidase (urNAG) level at the time of biopsy. Multivariate Cox analysis revealed that a higher level of eGFR was the most powerful predictor of allograft survival. Compared with those with eGFR≥60, the hazard ratio (HR) increased from 4.50 (95% CI: 1.03-19.71, p=0.0462) for patients with eGFR between 30 and 59 ml/min/1.73m2 to 9.14 (95% CI 1.97-42.45, P=0.0047) when eGFR decreased to 15 to 29 ml/min/1.73m2. Additionally, proteinuria and higher urRBP values (≥2.85mg/dl) were found to confer much worse survival rates for TG patients in multivariate Cox analysis. Male sex (HR 0.48, P=0.02) and HCV infection (HR 1.78, P=0.0499) were also found to be independent risk factors for worse allograft survival. Conclusion: Five clinical features—impaired renal function, higher proteinuria, higher urRBP level, male sex and HCV infection—are independent predictors of an unfavorable renal allograft outcome. urRBP is a simple and useful parameter that can add invaluable information for the clinical follow-up of patients with TG. [ABSTRACT FROM AUTHOR]

Background/Aims: Podocyte injury, especially podocyte apoptosis, plays a major role in early-stage diabetic nephropathy (DN). Swiprosin-1, also known as EF hand domain containing 2 (EFhd2), is a Ca2+-binding protein in different cell types. However, the function of swiprosin-1 in podocytes remains unknown. Methods: The expression and distribution of swiprosin-1 were investigated in the mouse renal glomerulus and conditionally immortalized mouse podocyte cell line MPC-5. The expression of swiprosin-1 was also detected in streptozotocin (STZ)-treated mice and MPC-5 cells treated with high glucose (HG). Nephrin and podocin were detected by immunohistochemistry and immunofluroscence. Collagen IV, transforming growth factor-β (TGF-β) and fibronectin mRNA expressions were assayed by real-time PCR. Apoptotic proteins and phosphorylation of p38 mitogen-activated protein kinase (MAPK) were detected by immunoblotting. Results: Swiprosin-1 was found to be expressed in podocytes of the mouse glomerulus and MPC-5 cells. Swiprosin-1 expression was increased in STZ-treated mice and MPC-5 cells treated with HG. In Swiprosin-1-/- diabetic mice, kidney/ body weight, urinary albumin, podocyte foot process effacement and glomerular basement membrane thickening were attenuated; the downregulation of nephrin and podocin expression in the glomerulus was inhibited; and the upregulation of collagen IV, TGF-β and fibronectin mRNA expression in the renal cortex was ameliorated as compared with those in diabetic swiprosin-1+/+ mice. In addition, the increased apoptosis of podocytes, proapoptotic protein expression and p38 phosphorylation in Swiprosin-1-/- diabetic mice were inhibited as compared with those in diabetic swiprosin-1+/+ mice. Knockdown of swiprosin-1 in MPC-5 cells reduced the apoptosis of podocytes, proapoptotic protein expression and p38 phosphorylation induced by HG. Targeted knockdown of p38 attenuated the increased apoptosis of MPC-5 cells over-expressing swiprosin-1. Conclusion: Swiprosin-1 expression in podocytes of the mouse glomerulus played a critical role in early-stage DN. Swiprosin-1 deficiency in early DN attenuated mitochondria-dependent podocyte apoptosis induced by hyperglycemia or HG via p38 MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Hypoxic/ischemic injury to the heart is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs (miRNAs) are involved in hypoxic/ischemic events, and δ-opioid receptor (DOR) activation is known to protect against hypoxic/ischemic injury, we speculated on the involvement of DOR activation in altering miRNA expression in the heart under hypoxic conditions. The present study aimed to test our hypothesis. Methods: Male Sprague Dawley rats were exposed to hypoxia (9.5-10% O2) for 1, 5, or 10 days with or without DOR activation. The target miRNAs were selected from TaqMan low-density array (TLDA) data and were further analyzed by quantitative real-time PCR. Results: We found that: 1) hypoxia alters the miRNA expression profiles depending on the hypoxic duration; 2) DOR activation shifts miRNA expression profiles in normoxic conditions and upregulates miR- 128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, and miR-338; and 3) DOR activation modifies hypoxia-induced changes in miRNA expression and increases the levels of miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, miR- 141, miR-200b, and miR-324-3p. For example, miR-196c-5p decreased by 50% while miR- 135a-5p increased 2.9 fold after 10 days under hypoxic conditions. Moreover, DOR activation further strengthened the hypoxia-induced increase of the levels of miR-7a-5p. When DOR was activated using UFP-512, the level of miR-107-3p significantly increased 1 day after the administration of UFP-512, but gradually decreased back to normal under normoxia. Conclusion: Hypoxia significantly modifies the miRNA profile in the heart, which can be mimicked or modified by DOR activation. Defining the targeted pathways that regulate the diverse cellular and molecular functions of miRNAs may provide new insights into potential therapies for hypoxic/ischemic injury of the heart. [ABSTRACT FROM AUTHOR]