Diabetic nephropathy (DN) remains a leading cause of end-stage renal failure (ESRD) in the US, presenting an urgent need to develop more sensitive biomarkers and new targets of therapy to halt the progression of DN. Using a microarray profile of a murine model of progressive CKD, we found that the renal expression of Rtn1a positively correlated with the severity of renal injury in animal models, including a model of DN. In addition, expression of RTN1A negatively correlated with estimated glomerular filtration rate (eGFR) in DN patients. Our preliminary data demonstrates that the increased expression of RTN1A, an ER-associated protein, induces ER stress and apoptosis of renal cells and that its reduced expression conversely attenuates tunicamycin-, hyperglycemia-, and albumin-induced ER-stress and apoptosis in vitro. In vivo, a global knockdown of Rtn1a attenuated proteinuria, glomerular hypertrophy, and mesangial expansion in STZ- induced diabetic mice, as well as renal fibrosis in an experimental model of ureteral obstruction. Based on these findings, we posit that RTN1 is a potential novel risk gene for kidney disease and that it promotes the progression of DN through ER stress. In this application we put forward the aims to determine the renal cell- specific role of RTN1A in different stages of DN and the molecular mechanism by which RTN1A induces ER stress and apoptosis under diabetic conditions. The proposed studies herein will confirm whether RTN1A may be developed as a potential drug target to treat DN.
Diabetic nephropathy (DN) is the most common cause of end-stage renal disease in the US. However current regimen provides only partial therapeutic effects and the incidence and prevalence of DKD remains high, suggesting that the key pathogenic mechanisms driving DKD progression are not adequately inhibited by current treatments. Therefore, better understanding of mechanisms that mediate the early stage of DKD and drive the disease progression is urgently required to identify novel preventive and therapeutic measures for DKD patients.
