title: Normalization of renal aquaporin-2 water channel expression by fosinopril, valsartan, and combination therapy in congestive heart failure: a new mechanism of action.
abstract: This study investigated the effect of fosinopril (Fos), valsartan (Val), and combination of both drugs (Fos + Val) on the cardiac and renal expression of aquaporin-1 (AQP1) and aquaporin-2 (AQP2) in congestive heart failure (CHF). A rat model of CHF was created by ligating the left anterior descending coronary artery to induce acute myocardial infarction (AMI). Rats were treated by Fos, Val, or Fos + Val for 4 weeks. In renal medulla and cortex, AMI was associated with 2.2- and 1.8-fold increase in AQP2 mRNA expression when compared with Sham-operated rats (medulla: 23.6 +/- 2.8 vs. 52.3 +/- 8.7%; P<0.001; cortex: 19.4 +/- 3.9 vs. 35.5 +/- 7.1%; P<0.05). All the treatment regimens were able to normalize AQP2 transcription in the renal medulla (Fos, 19.9 +/- 4.9%; Val, 22.8 +/- 4.9%; Fos + Val, 20.1 +/- 5.1%; P=NS vs. Sham) and in the cortex (Fos, 21.2 +/- 6.7%; Val, 20.4 +/- 6.0%; Fos + Val, 18.9 +/- 7.5%; P=NS vs. Sham). Similarly, the AQP2 protein expression increased by 2.1-fold after CHF (P<0.05), and was normalized by the treatment regimens (Sham, 0.57 +/- 0.19%; CHF, 1.22 +/- 0.45%; Fos, 0.39 +/- 0.36%; Val, 0.46 +/- 0.34%; Fos + Val, 0.36 +/- 0.15%; all P<0.05 vs. CHF). These treatment regimens also prevented the increase in body weight as found in untreated CHF rats (analysis of variance P<0.05). The renal and cardiac AQP1 gene and protein expressions were unaltered in CHF or by medical therapy. There was no observed cardiac AQP2 expression in all the study groups. Treatment with Fos, Val, or combination therapy was effective in preventing the upregulation of renal AQP2 gene and protein expressions in CHF rats caused by AMI.
authors.affiliation: Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. cmyu@cuhk.edu.hk
authors.forename: Cheuk-Man
authors.initials: CM
authors.lastname: Yu
authors.forename: Kevin
authors.initials: K
authors.lastname: Wing-Hon Lai
authors.forename: Pik-Shan
authors.initials: PS
authors.lastname: Li
authors.forename: Kar-Yee
authors.initials: KY
authors.lastname: Lam
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
authors.forename: Kar-Neng
authors.initials: KN
authors.lastname: Lai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D051399:Aquaporin 2; D020346:Aquaporins / Q000096:biosynthesis*; D004359:Drug Therapy, Combination; D017328:Fosinopril / Q000008:administration & dosage*; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D007679:Kidney Medulla / Q000378:metabolism / Q000473:pathology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage*; D014633:Valine / Q000008:administration & dosage* / Q000031:analogs & derivatives; D000068756:Valsartan
chemical_list: D000959:Antihypertensive Agents; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D020346:Aquaporins; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine; D017328:Fosinopril