Urinary nephrin is a potential non-invasive biomarker of disease. To date, however, most studies of urinary nephrin have been conducted in animal models of diabetic nephropathy, and correlations between urinary nephrin-to-creatinine ratio and other parameters have yet to be evaluated in animal models or patients of kidney disease with podocyte dysfunction. We hypothesized that urinary nephrin-to-creatinine ratio can be up-regulated and is negatively correlated with renal nephrin mRNA levels in animal models of kidney disease, and that increased urinary nephrin-to-creatinine ratio levels are attenuated following administration of glucocorticoids. In the present study, renal nephrin mRNA, urinary nephrin-to-creatinine ratio, urinary protein-to-creatinine ratio, and creatinine clearance ratio were measured in animal models of adriamycin nephropathy, puromycin aminonucleoside nephropathy, anti-glomerular basement membrane glomerulonephritis, and 5/6 nephrectomy. The effects of prednisolone on urinary nephrin-to-creatinine ratio and other parameters in puromycin aminonucleoside (single injection) nephropathy rats were also investigated. In all models tested, urinary nephrin-to-creatinine ratio and urinary protein-to-creatinine ratio increased, while renal nephrin mRNA and creatinine clearance ratio decreased. Urinary nephrin-to-creatinine ratio exhibited a significant negative correlation with renal nephrin mRNA in almost all models, as well as a significant positive correlation with urinary protein-to-creatinine ratio and a significant negative correlation with creatinine clearance ratio. Urinary protein-to-creatinine ratio exhibited a significant negative correlation with renal nephrin mRNA. Following the administration of prednisolone to puromycin aminonucleoside (single injection) nephropathy rats, urinary nephrin-to-creatinine ratio was significantly suppressed and exhibited a significant positive correlation with urinary protein-to-creatinine ratio. In addition, the decrease in number of glomerular Wilms tumor antigen-1-positive cells was attenuated, and urinary nephrin-to-creatinine ratio exhibited a significant negative correlation in these cells. In conclusion, these results suggest that urinary nephrin-to-creatinine ratio level is a useful and reliable biomarker for predicting the amelioration of podocyte dysfunction by candidate drugs in various kidney disease models with podocyte dysfunction. This suggestion will also be validated in a clinical setting in future studies.
Renal inflammation is a final common pathway of chronic kidney disease (CKD), and its progression can be used to effectively gauge the degree of renal dysfunction. Inflammatory mechanisms contribute to glomerulosclerosis and tubulointerstitial fibrosis, which are hallmarks of CKD leading to end-stage renal disease. Receptor-interacting protein kinase 2 (RIP2) is largely committed to nucleotide-binding oligomerization domain signaling as a direct effector and transmits nuclear factor-kB (NF-kB)-mediated proinflammatory cytokine production. In the present study, we hypothesized that if inflammation via RIP2 and NF-kB signaling plays an important role in renal failure, then the anti-inflammatory effect of RIP2 inhibitors should be effective in improving CKD. To determine its pharmacologic potency, we investigated the renoprotective properties of the novel RIP2 inhibitor AS3334034 [7-methoxy-6-(2-methylpropane-2-sulfonyl)-N-(4-methyl-1H-pyrazol-3-yl)quinolin-4-amine] in uninephrectomized adriamycin-induced CKD rats. Six weeks' repeated administration of AS3334034 (10 mg/kg, once daily) significantly reduced urinary protein excretion and prevented the development of glomerulosclerosis and tubulointerstitial fibrosis. In addition, AS3334034 showed beneficial effects on renal function, as demonstrated by a decrease in levels of plasma creatinine and blood urea nitrogen and attenuation of a decline in creatinine clearance. Furthermore, AS3334034 significantly attenuated inflammation, renal apoptosis, and glomerular podocyte loss. These results suggest that the RIP2 inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect and is therefore potentially useful in treating patients with CKD. SIGNIFICANCE STATEMENTThe receptor-interacting protein kinase 2 (RIP2) inhibitor AS3334034 suppresses the progression of chronic renal failure via an antiinflammatory effect, suggesting that the nucleotide-binding oligomerization domain-RIP2 axis might play a crucial role in the pathogenesis of inflammatory kidney diseases. AS3334034 is expected to be potentially useful in the treatment of patients with chronic kidney disease.
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