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RENIN-ANGIONTENSIN-ALDOSTERONE-SYSTEM (RAAS) BLOCKERS IN DIABETIC NEPHROPATHY (DN)

RENIN-ANGIONTENSIN-ALDOSTERONE-SYSTEM (RAAS) BLOCKERS IN DIABETIC NEPHROPATHY (DN). N óra F anni Bánki SE-MTA “ Lendulet ” Diabetes Research Group , 1 st Dep. of Pediatrics, Academic Research Group for Pediatrics and Nephrology , Semmelweis University, Budapest

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RENIN-ANGIONTENSIN-ALDOSTERONE-SYSTEM (RAAS) BLOCKERS IN DIABETIC NEPHROPATHY (DN)

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  1. RENIN-ANGIONTENSIN-ALDOSTERONE-SYSTEM (RAAS) BLOCKERS IN DIABETIC NEPHROPATHY (DN) Nóra FanniBánki SE-MTA “Lendulet” Diabetes Research Group, 1st Dep. of Pediatrics, Academic Research Group forPediatrics and Nephrology, Semmelweis University, Budapest 2012 V4 Academies Forum Mátraháza, 26.10.2012 fannibanki@yahoo.com

  2. Introduction • By 2035 the number of diabetic patients will reach approximately 400 million (IDF – 2011). • 35-40% of diabetic patients develop DN within 15-20 years after the diagnosis (USRDS – 2010). • The 2012 American Diabetes Association protocol recommends the use of ACE inhibitors or ARBs in the case of microalbuminuria (ADA – 2012). • Renal RAAS is activated in diabetes and angiotensin II (AngII) level is increased (Ribiero et al – 2008). fannibanki@yahoo.com

  3. Sigma-1 receptor (Sigma-1R) • The Sigma-1R is expressedin several tissues and organs (Pontén, 2009). • Renal localization and function are yet unknown. • The activation of Sigma-1R induces the Akt – endothelial nitric oxidesynthase (eNOS) pathway • protective against hypoxic injury in the heart and brain (Bhuiyan, 2011). • preserves the Na/K ATPase (NKA) in its physiological location(Lei, 2011).

  4. Previous experiments • In Streptozotocin (STZ) induced diabetic rats: • elevatedexpression and mislocation of renal NKA. • exogenlygivenAngIIcausesfurtherprogression of DN. • Sigma-1R agonsitsarerenoprotectiveagainstischemia-reperfusioninjury. fannibanki@yahoo.com

  5. Aim To investigate the effect of different RAAS blockers on the pathophysiology of DN and the Sigma-1R – Akt - NKA system. Angiotensinogen AngI AngII ANG Receptor ACE Aldosterone losartan spironolactone eplerenone enalapril fannibanki@yahoo.com

  6. Methods • After 5 weeks of STZ-induced (60mg/kgiv.)diabetes, Wistar rats were treated daily p.o.for 2 weeks with • enalapril (40 mg x kg-1 x day-1; n=6), • losartan (20 mg x kg-1 x day-1; n=6), • spironolactone (50 mg x kg-1 x day-1; n=6), • epleronone (50 mg x kg-1 x day-1; n=6), • saline (n=6). • Blood pressure was monitored non-invasively before and after treatment with a CODA tail-cuff system. • Serum and urine parameters were measured and histological scanning of the excised kidney was performed. • Protein levels and intrarenal localization of Sigma-1R-Akt-NKAwere evaluated. fannibanki@yahoo.com

  7. Mean arterial blood pressure (MAP) and heart rate * p<0,05 vs. Control; § p<0,05 vs. D; n=6 fannibanki@yahoo.com

  8. Laboratory parameters * p<0,05 vs. Control; § p<0,05 vs. D; n=6; Se – serum, BUN – blood urea nitrogen; LDL – low density lipoprotein fannibanki@yahoo.com

  9. Renal histology Control Diabetes (D) Arterial hyalinisation Mesangial matrix expansion D + Enalapril D + Losartan D + Spironolactone D + Eplerenone * p<0,05 vs. Control; § p<0,05 vs. D; n=6; PAS staining; 40x magnification; scalebar: 50 μm fannibanki@yahoo.com

  10. Renal Sigma-1R, pAkt, NKA * p<0,05 vs. Control; ** p<0,01 vs. Control; § p<0,05 vs. D; n=6

  11. Renal Sigma-1R and NKA localization Green – NKA, Red – S1R, Blue – nuclei, 63x magnification

  12. Summary fannibanki@yahoo.com

  13. Conclusion • RAAS inhibitor treatmentcan be usedtopreventtheprogression of DN in these doses without blood pressure lowering side effects in rats. • Aldosterone antagonist monotherapycouldbe beneficial in the prevention of STZ-induced DN. • The renal Sigma-1R – Akt – NKA pathwaymay play a roleinthepathophysiology of DN and couldserveas a newtherapeutictarget of RAAS inhibitors. fannibanki@yahoo.com

  14. Plans for the future • Introduction of type 2 diabetic animal models (Zucker rats, db/db mice). • Use of Sigma-1R agonists (antidepressant fluvoxamine), antagonists and other RAAS inhibitors (ramipril ect.). • Investigation of depressive behavior with the forced swim test ect. • Evaluation of the NOS system. • In vivo visualisation with multiphoton microscopy. * p<0,05 vs. Control; § p<0,05 vs. D; n=6

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