title: Intrarenal Renin-Angiotensin system is upregulated in experimental model of progressive renal disease induced by chronic inhibition of nitric oxide synthesis.
abstract: Locally generated angiotensin II (AngII) may be involved in the pathogenic mechanisms of chronic renal diseases. Renal expression of AngII and other components of the renin-angiotensin system (RAS) were analyzed by immunohistochemistry and Western blot in a model of chronic progressive nephropathy induced by inhibition of nitric oxide synthesis. Renal injury was evaluated by histology and albumin excretion. Systemic RAS status was evaluated through plasma renin activity (PRA) and plasma AngII concentration. In addition, the effects of enalapril, losartan, and mycophenolate mofetil (MMF) on AngII expression in animals with chronic renal disease was also analyzed. Plasma renin activity and plasma AngII were not different between rats with nephropathy and controls (2.08 +/- 0.7 versus 2.03 +/- 0.5 ng/ml/h and 94.3 +/- 18 versus 78.9 +/- 16 fmol/ml, respectively). However, rats with chronic progressive nephropathy showed augmented renal content of angiotensinogen protein (13.5 +/- 3.5 versus 2.2 +/- 0.4 pixels in control rats; P < 0.05), enhanced expression of cathepsin D-a renin-like enzyme-in cortical collecting tubules (103.5 +/- 27.0 versus 66.2 +/- 3.6 cells/mm2 in controls; P < 0.01), and increased expression of AT1 receptor in interstitium (54.7 +/- 7.8 versus 1.3 +/- 0.4 cells/mm2 in controls; P < 0.001). Kidney angiotensin-converting enzyme content did not differ among the groups. Notably, an increased number of interstitial cells expressing AngII was detected in the renal interstitium (9.5 +/- 1.6 versus 1.7 +/- 0.6 cells/mm2 in controls; P < 0.05). Rats treated with Nomega-nitro-L-arginine-methyl-esther and losartan presented a decreased local AngII formation, in contrast to its known effect on plasma AngII. Moreover, mycophenolate mofetil lowered interstitial AngII expression, suggesting that inflammatory signaling may be involved in interstitial AngII generation. This study demonstrates the upregulation of local RAS in the kidney in a model of chronic progressive nephropathy.
authors.affiliation: Renal Pathophysiology Laboratory, Nephrology Division, University of São Paulo, Brazil.
authors.forename: Miguel Luis
authors.initials: ML
authors.lastname: Graciano
authors.forename: Rita de Cassia
authors.initials: Rde C
authors.lastname: Cavaglieri
authors.forename: Humberto
authors.initials: H
authors.lastname: Dellê
authors.forename: Wagner Vasquez
authors.initials: WV
authors.lastname: Dominguez
authors.forename: Dulce Elena
authors.initials: DE
authors.lastname: Casarini
authors.forename: Denise Maria Avancini Costa
authors.initials: DM
authors.lastname: Malheiros
authors.forename: Irene L
authors.initials: IL
authors.lastname: Noronha
mesh_terms: D000418:Albumins / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000378:metabolism; D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure; D015153:Blotting, Western; D002402:Cathepsin D / Q000378:metabolism; D004656:Enalapril / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005921:Glomerulonephritis / Q000473:pathology; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000418:Albumins; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D000808:Angiotensinogen; D009569:Nitric Oxide; D004656:Enalapril; D012083:Renin; D002402:Cathepsin D; D009173:Mycophenolic Acid; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester