Nephroprotective Efficacy of RAS Blockade in Mice Carrying R140Q Podocin Mutation

<p>INTRODUCTION:NPHS2 mutations cause hereditary nephrotic syndrome and progressive renal failure.We recently generated an inducible knock-in mouse model carrying R140Q,the analogue of the most common human mutation R138Q.These mice develop FSGS with nephrotic syndrome and progressive renal failure.Here we tested the efficacy of early and delayed RAS blockade in this model of hereditary podocyte disease.</p> <p>METHODS:In C57BL/6 mice with Nphs2Flox/R140Q/Cre+ genotype,hemizygosity for mutant podocin was induced by tamoxifen injection.Animals received combined high-dose ACE inhibition and AT1 receptor blockade(ramipril+candesartan 10mg/kg each,R+C)or remained untreated.Treatment was started either prophylactically(P)at time of induction or with a 4-week delay(D).Animals were either sacrificed after 5 wks(9 wks in D) or observed open-end.</p> <p>RESULTS:Induction of R140Q-podocin hemizygosity caused massive proteinuria peaking at 4 wks,followed by a gradual decrease as progressive renal failure developed.In the P animals,RAS blockade persistently inhibited proteinuria(13%of untreated animals at 4 wks,p<0.005).In the D group,proteinuria sharply decreased upon RAS blockade.Three-month survival was 31% in the untreated,67% in the D and 100% in the P group respectively(p<0.05).<br>Podocin protein abundance was almost totally lost in both untreated and treated animals,despite preserved or even increased mRNA expression.P group animals retained a higher number of podocytes per glomerulus and lower glomerulosclerosis and tubolointerstitial fibrosis indices than the untreated animals.In the D animals,histopathological lesions were slightly less marked at 9 wks than in the untreated animals at 5 wks.</p> <p>CONCLUSIONS:In mice carrying the most common human podocin mutation,RAS blockade attenatues proteinuria,podocyte loss and glomerulosclerosis despite persistently increased degradation of mutant podocin protein.Renal failure is delayed and survival prolonged.Treatment is more effective when applied prophylactically than when started in established nephropathy.Our findings indicate that early RAS blockade may provide effective nephroprotection in this hereditary podocytopathy.</p> <p> </p