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Pharmacological Nephroprotection in a Novel Mouse Model of Hereditary Nephrotic Syndrome

Pharmacological Nephroprotection in a Novel Mouse Model of Hereditary Nephrotic Syndrome. Ivana Simic, Mansoureh Tabatabaeifar, Helga Denc, Tanja Wlodkowski, Geraldine Mollet, Corinne Antignac, Franz Schaefer Division of Pediatric Nephrology, University of Heidelberg

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Pharmacological Nephroprotection in a Novel Mouse Model of Hereditary Nephrotic Syndrome

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  1. Pharmacological Nephroprotection in a Novel Mouse Model of Hereditary Nephrotic Syndrome Ivana Simic, Mansoureh Tabatabaeifar, Helga Denc, Tanja Wlodkowski, Geraldine Mollet, Corinne Antignac, Franz Schaefer Division of Pediatric Nephrology, University of Heidelberg Department of Human Genetics, Hopital Necker, Paris 25th European Congress of Pathology, Lisbon, 31 August – 4 September 2013

  2. N-term C-term R138Q The NPHS2 Gene and Hereditary Nephrotic Syndrome • Mutations in the NPHS2 gene, encoding podocin, cause autosomal recessive steroid-resistant nephrotic syndrome • R138Q, the most common podocin mutation in Europeans, causes early disease onset and rapid progression to end-stage renal disease • Recently, we generated and characterized an inducible knock-in mouse carrying the R140Q podocin mutation, the murine analogue of the most common human mutation R138Q

  3. Cre Cre Cre Cre Creation of a Conditional Knock-in Mouse Model of R140Q Mutation X Bl6 Bl6 Nphs2R140Q/+ Nphs2lox2/lox2 Cre+/+ Nphs2lox2/R140Q Cre+ Tamoxifen induction Nphs2R140Q/-

  4. Tamoxifen-induced mice received 10 mg/kg/day of: ACE inhibitor Ramipril (R) AT1 receptor blocker Candesartan (C) the combination of Ramipril and Candesartan (R+C) non-RAS antihypertensive amlodipine (A) Control groups: Tamoxifen induction (sick controls) Vehicle injections (healthy controls) Prophylactic RAS Blockade in a Conditional Knock-in Mouse Model of R140Q Mutation

  5. ** ** * *** ** *** *** *** *** *** *** *** *** *** Blood Pressure Effect of RAS Antagonists vs. Amlodipine * p<0.05; ** p<0.01; *** p<0.001

  6. Markedly Attenuated Proteinuria in Podocin R140Q Knock-In Mice Treated with RAS Antagonists

  7. Normoalbuminemia in Podocin R140Q Knock-In Mice Treated with RAS Antagonists * p<0.05; ** p<0.01; *** p<0.0001

  8. Reduced Plasma Creatinine Levels in All Treated Animals

  9. Subtotal Loss of Podocin Protein in All Induced Animals Irrespective of Pharmacological Treatment 4 WKS Control R C R+C A kDa Podocin 37 GAPDH 37

  10. untreated healthy Amlodipine R+C The Loss of Podocin Signal at Immunofluorescence Analysis

  11. * * p>0.05 comparing to both sick untreated and healthy animals Preserved Podocin mRNA Expression in All Induced Animals

  12. A. * ** *** **** B. * p>0.05; ** p<0.05; *** p<0.01; **** p<0.001 PAS staining of renal tissue in induced animals: A. Untreated (notable GS); B. Mice treated with R+C. Attenuated Glomerulosclerosis in Animals Treated with RAS Antagonists

  13. p>0.05 A. B. Insignificantly Attenuated Tubulointerstitial Fibrosis in Animals Treated with RAS Antagonists Sirius-Red-staining: A. Untreated animals; B. Mice treated with R+C.

  14. A. * *** ** ** B. * p<0.05; ** p<0.01; *** p<0.001 WT1 immunostaining of glomeruli of induced mice: A. Untreated (reduced podocyte number); B. Treated with R+C. Improved Podocyte Survival in Animals Treated with RAS Antagonists

  15. Summary • RAS antagonists markedly attenuate proteinuriain mice hemizygous for podocin R140Q mutation • After 4 weeks, mice receiving R+C were normo-albuminemic and serum creatinine was increased less than in untreated or animals treated with Amlodipine • Reduced glomerulosclerosis and better podocyte survival in animals treated with RAS antagonists • RAS blockade provides effective pharmacological nephroprotection in this hereditary podocytopathy model

  16. Dr. Ivana Simic Dr. Mansoureh Tabatabaeifar Tanja Wlodkowski Dr. Helga Denc Prof. Dr. Franz Schaefer Hopital Necker, France Dr. Geraldine Mollet Prof. Dr. Corinne Antignac

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