title: Combination of direct renin inhibition with angiotensin type 1 receptor blockade improves aldosterone but does not improve kidney injury in the transgenic Ren2 rat.
abstract: Enhanced renin-angiotensin-aldosterone system (RAAS) activation contributes to proteinuria and chronic kidney disease by increasing glomerular and tubulointerstitial oxidative stress, promotion of fibrosis. Renin activation is the rate limiting step in angiotensin (Ang II) and aldosterone generation, and recent work suggests direct renin inhibition improves proteinuria comparable to that seen with Ang type 1 receptor (AT(1)R) blockade. This is important as, even with contemporary use of AT(1)R blockade, the burden of kidney disease remains high. Thereby, we sought to determine if combination of direct renin inhibition with AT(1)R blockade in vivo, via greater attenuation of kidney oxidative stress, would attenuate glomerular and proximal tubule injury to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat with increased tissue RAS activity and higher serum levels of aldosterone, which manifests hypertension and proteinuria. Ren2 rats were treated with renin inhibition (aliskiren), AT(1)R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic pressure (SBP), circulating aldosterone, proteinuria and greater urine levels of the proximal tubule protein excretory marker beta-N-acetylglucosaminidase (β-NAG). These functional and biochemical alterations were accompanied by increases in kidney tissue NADPH oxidase subunit Rac1 and 3-nitrotyrosine (3-NT) content as well as fibronectin and collagen type III. These findings occurred in conjunction with reductions in the podocyte-specific protein podocin as well as the proximal tubule-specific megalin. Further, in transgenic animals there was increased tubulointerstitial fibrosis on light microscopy as well as ultrastructural findings of glomerular podocyte foot-process effacement and reduced tubular apical endosomal/lysosomal activity. Combination therapy led to greater reductions in SBP and serum aldosterone, but did not result in greater improvement in markers of glomerular and tubular injury (i.e. β-NAG) compared to either intervention alone. Further, combination therapy did not improve markers of oxidative stress and podocyte and proximal tubule integrity in this transgenic model of RAAS-mediated kidney damage despite greater reductions in serum aldosterone and BP levels.
authors.affiliation: Harry S. Truman VA Medical Center, University of Missouri-Columbia School of Medicine, Columbia, MO 65211, USA. whaleyconnella@health.missouri.edu
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Ravi
authors.initials: R
authors.lastname: Nistala
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pulakat
authors.forename: Catherine
authors.initials: C
authors.lastname: Sinak
authors.forename: Bonnie
authors.initials: B
authors.lastname: Locher
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis / Q000378:metabolism*; D000577:Amides / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D005650:Fumarates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012083:Renin / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D000092502:Renin Inhibitors
chemical_list: D000450:Aldosterone; D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D005650:Fumarates; D044140:Receptor, Angiotensin, Type 1; D012083:Renin; D013777:Tetrazoles; D014633:Valine; D000068756:Valsartan; D000092502:Renin Inhibitors; C535029:Ren2 protein, rat; C446481:aliskiren