A reduction of unilateral ureteral obstruction-induced renal fibrosis by a therapy combining valsartan with aliskiren.
The protective effect of combination therapy with valsartan and aliskiren against renal fibrosis remains to be defined. This study was undertaken to examine the protective effects of the combination of valsartan and aliskiren against renal fibrosis induced by unilateral ureteral obstruction (UUO). Combination therapy with valsartan (15 mg·kg(-1)·day(-1)) and aliskiren (10 mg·kg(-1)·day(-1)), valsartan monotherapy (30 mg·kg(-1)·day(-1)), and aliskiren monotherapy (20 mg·kg(-1)·day(-1)) all significantly ameliorated the increase in blood urea nitrogen and the degree of hydronephrosis determined by the increase in weight and length of the obstructed kidney. The dose titration study and blood pressure measurement confirmed that the combination therapy provided a greater benefit independent of the vasodilatory effect. There were no significant changes in serum levels of creatinine, sodium, and potassium in UUO rats and any treatment groups. Combination therapy also attenuated UUO-related increases in the scores of tubular dilatation, interstitial volume, interstitial collagen deposition, α-smooth muscle actin, the activation of ERK 1/2, the infiltration of monocytes/macrophages, the mRNA expression of snail-1, and transforming growth factor-β1 to a greater extent compared with aliskiren or valsartan used alone. The mRNA expression of renin and the (pro)renin receptor significantly increased after UUO. Combination therapy and monotherapy of valsartan and aliskiren had a comparable enhancing effect on the mRNA expression of renin, whereas all these treatments did not affect the expression of the (pro)renin receptor. In conclusion, a direct renin inhibitor in conjunction with an angiotensin II receptor blocker exerts increased renal protection against renal fibrosis and inflammation during obstruction over either agent alone.
Wu
Wen-Pyng
WP
Graduate Institute of Clinical Medical Science, China Medical University, China.
Chang
Chi-Hao
CH
Chiu
Yung-Tsung
YT
Ku
Cheng-Lung
CL
Wen
Mei-Chin
MC
Shu
Kuo-Hsiung
KH
Wu
Ming-Ju
MJ
D000199:Actins / Q000096:biosynthesis; D000577:Amides / Q000627:therapeutic use*; D019412:Anatomy, Cross-Sectional; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism; D004359:Drug Therapy, Combination; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D005650:Fumarates / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics; D007677:Kidney Function Tests; D008297:Male; D020556:Neutrophil Infiltration; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D013777:Tetrazoles / Q000627:therapeutic use*; D014157:Transcription Factors / Q000096:biosynthesis; D014517:Ureteral Obstruction / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan
D000199:Actins; D000577:Amides; D000959:Antihypertensive Agents; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; D005650:Fumarates; D000071250:Snail Family Transcription Factors; D013777:Tetrazoles; D014157:Transcription Factors; D014633:Valine; D000068756:Valsartan; C000604450:Snai2 protein, rat; C498862:Acta2 protein, rat; C446481:aliskiren