Wnt4 is a secreted growth factor associated with renal tubulogenesis. Our previous studies identified that renal and urinary Wnt4 are upregulated following ischemia-reperfusion injury in mice, but the roles of Wnt4 in other forms of acute kidney injury (AKI) remain unclear. Here, we investigated the changes in Wnt4 expression using a cisplatin-induced AKI model. We found that renal and urinary Wnt4 expression increased as early as 12 hours, peaked at day 4 following cisplatin-induced AKI and was closely correlated with histopathological alterations. By contrast, the serum creatinine level was significantly elevated until day 3, indicating that Wnt4 is more sensitive to early tubular injury than serum creatinine. In addition, renal Wnt4 was co-stained with aquaporin-1 and thiazide-sensitive NaCl cotransporter, suggesting that Wnt4 can detect both proximal and distal tubular injuries. These data were further confirmed in a clinical study. Increased urinary Wnt4 expression was detected earlier than serum creatinine and eGFR in patients with contrast-induced AKI after vascular intervention. This study is the first to demonstrate that increased expression of renal and urinary Wnt4 can be detected earlier than serum creatinine after drug-induced AKI. In particular, urinary Wnt4 can potentially serve as a noninvasive biomarker for monitoring patients with tubular injury.

Since urine samples more directly reflect kidney alterations and damage than blood samples, we investigated whether urine anti-PLA2R antibody (uPLA2R-Ab) could be utilized similarly to serum anti-PLA2R antibody (sPLA2R-Ab) as a noninvasive biomarker of idiopathic membranous nephropathy (IMN). In this study, we performed a qualitative analysis using an indirect immunofluorescence test (IIFT) and measured uPLA2R-Ab and sPLA2R-Ab concentrations using an enzyme-linked immunosorbent assay (ELISA) in 28 patients with biopsy-proven IMN and 12 patients with secondary membranous nephropathy (SMN). Overall, 64.3% (n=18) of patients with IMN had IIFT-positive sPLA2R-Ab, 67.9% (n=19) of patients with IMN had IIFT-positive uPLA2R-Ab, and none of the SMN patients had IIFT-positive sPLA2R-Ab or uPLA2R-Ab. The titers of the anti-PLA2R antibody from the IMN patients in the urine (10.72±22.24 RU/μmol, presented as uPLA2R-Ab/urine creatinine) and serum (107.36±140.93 RU/ml) were higher than those from the SMN patients (0.51±0.46 RU/μmol, 0.008±0.029 RU/ml, respectively, p<0.05). Statistical analyses indicated that there were positive correlations between uPLA2R-Ab and gPLA2R, sPLA2R-Ab or urinary protein and negative correlations between uPLA2R-Ab and serum albumin in patients with IMN. In conclusion, uPLA2R-Ab is a novel biomarker of IMN. sPLA2R-Ab combined with uPLA2R-Ab might be more helpful for diagnosis and activity in PLA2R associated MN.

Background/purpose: Understanding the mechanisms of protecting the kidneys from injury is of great importance because there are no effective therapies that promote repair and the kidneys frequently do not repair adequately. Evidence has shown that erythropoietin (EPO) has a vital renoprotective role, independent of its erythropoietic effect. However, whether EPO can contribute to kidney repair after injury and the potential mechanisms are not fully understood.Methods: To investigate the renoprotective mechanism of EPO, a kidney ischemia/reperfusion injury (IRI) model was induced in adult male Sprague-Dawley rats. The rats were subsequently randomly treated with EPO or a vehicle 6 hours after the kidney IRI. The rats were sacrificed on Day 3, Day 5, and Day 7 post kidney IRI. Renal function and histological alterations were examined. Renal interstitial macrophage infiltration, cell proliferation, apoptosis, and angiogenesis were evaluated by immunostaining. Furthermore, the effects of EPO on the Wnt/beta-catenin pathway and IRI-related micro-RNAs were investigated.Results: The administration of EPO significantly improved renal function and reduced tubular injury. Furthermore, EPO treatment significantly prevented tubular cell apoptosis and promoted cell proliferation after IRI. Erythropoietin significantly suppressed macrophage infiltration, compared to the vehicle. In addition, treatment with EPO markedly prevented the loss of microvasculature. We have also demonstrated that, compared to the vehicle, EPO administration enhanced the expression of Wnt7b and beta-catenin, and downregulated miR-21, -214, -210, and -199a.Conclusion: Erythropoietin protects the kidneys against IRI by attenuating injury of the renal microvasculature and tubule epithelial cells, by promoting Wnt/beta-catenin pathway activation, and by regulating miRNA expression. Copyright (C) 2015, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.

http://dx.doi.org/10.1016/j.jfma.201 0929-6646/Copyright a 2015, Elsevier Background/purpose: Understanding the mechanisms of protecting the kidneys from injury is of great importance because there are no effective therapies that promote repair and the kidneys frequently do not repair adequately. Evidence has shown that erythropoietin (EPO) has a vital renoprotective role, independent of its erythropoietic effect. However, whether EPO can contribute to kidney repair after injury and the potential mechanisms are not fully understood. Methods: To investigate the renoprotective mechanism of EPO, a kidney ischemia/reperfusion injury (IRI) model was induced in adult male SpragueeDawley rats. The rats were subsequently randomly treated with EPO or a vehicle 6 hours after the kidney IRI. The rats were sacrificed on Day 3, Day 5, and Day 7 post kidney IRI. Renal function and histological alterations were examined. Renal interstitial macrophage infiltration, cell proliferation, apoptosis, and angiogenesis were evaluated by immunostaining. Furthermore, the effects of EPO on the Wnt/b-catenin pathway and IRI-related micro-RNAs were investigated. Results: The administration of EPO significantly improved renal function and reduced tubular injury. Furthermore, EPO treatment significantly prevented tubular cell apoptosis and promoted cell proliferation after IRI. Erythropoietin significantly suppressed macrophage infiltration, compared to the vehicle. In addition, treatment with EPO markedly prevented the loss of microvasculature. We have also demonstrated that, compared to the vehicle, EPO administration enhanced the expression of Wnt7b and b-catenin, and downregulated miR-21, -214, -210, and -199a.

BACKGROUND:Previous studies have demonstrated that angiotensin Type I receptor blockade (ARB) reduces proteinuria, reverses glomerular injury and glomerulosclerosis in rat models of diabetic nephropathy and glomerulonephritis. However, the cellular and molecular mechanisms are unclear. To investigate the role of cells of the bone marrow (BM) in glomerular repair seen during ARB administration, we induced progressive glomerulosclerosis in enhanced green fluorescent protein BM chimeric rats by a single injection of anti-Thy 1.1 monoclonal antibody, followed by unilateral nephrectomy.METHODS:Cohorts of rats received valsartan or no treatment from Week 2 to Week 8 after induction of disease. Renal function, urinary protein excretion and histological changes were examined 8 weeks after anti-Thy-1.1 monoclonal antibody injection.RESULTS:Valsartan administration improved renal function, reduced severity of glomerulosclrosis and markedly reduced mortality. Valsartan administration promoted regeneration of the glomerular tuft, lowered proteinuria and resulted in enhanced vascular endothelial growth factor (VEGF) expression in the cortex and glomerular tuft. In addition, valsartan promoted increased recruitment of BM-derived cells (BMDCs) many of which expressed VEGF and likely contributed directly to glomerular repair. Nearly all BMDCs recruited to the glomerulus expressed the monocyte/macrophage marker CD68.CONCLUSIONS:In conclusion, the data shows that ARB by valsartan prevents glomerulosclerosis progression by enhancing glomerular capillary repair which is associated with the recruitment of VEGF producing 'reparative' monocytes and macrophages from the BM.

Objective To investigate the protective role of bone marrow-derived stem cells (BMDSCs) in progressive glomerulosclerosis rats,and to observe whether BMDSCs promote glomenlar repair and regeneration.Methods Progressive glomerulosclerosis was induced in enhanced green fluorescent protein (EGFP) bone marrow chimeric rats by injecting with anti-Thy1.1 antibody,followed by unilateral nephrectomy.Subsequently,these rats were treated with either BMDSCs infusion (treatment group,10 rats) or phosphate-buffered saline (untreated group,1O rats).Renal function and histological alterations were examined at week 12 after Thy1.1 antibody injection.Repair and regeneration of glomerular endothelial cells was detected by immunofluorescence.Results Only 3 rats survived in untreated group,other 7 rats died at week 2,7,9,11 after antibody injection.In treatment group,9 rats survived at week 12,only 1rat died at week 10.The BUN and Scr were significantly lower in treatment group as compared to untreated group [BUN(43.55±29.06) vs (76.58±66.19) mmol/L,Scr (138.79±75.14) vs (233.38±164.43) μmol/L].Proteinuria was not significantly different between two groups at day 3,7,14 and 28,while it was significantly decreased at day 42,56 and 84 in treatment group compared with untreated group.Light microscopy showed that there was severe diffuse mesangial cell proliferation,mesangial matrix expansion and glomerulosclerosis in untreated group,and such changes were ameliorated in treatment group.The mesangial expansion index and glomerular sclerosis index in untreated group was significantly higher than those in treatment group.More BMDCs were recruited into the glomeruli and differentiated into glomerular endothelial cells in treatment group as compared with untreated group.Double immunofluorescence stain also demonstrated that BMDSCs infusion promoted glomerular capillary repair and regeneration.Conclusion BMDSCs infusion can improve renal function and histological changes,and promote the repair and regeneration of glomerular capillary.