1 / 14

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

lana
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related