trandolapril and Renal-Insufficiency--Chronic

Our previous studies in rats with ablation nephrectomy have shown similar cardiorenal protective effects of renin-angiotensin system (RAS)-dependent treatment (combination of angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker) and RAS-independent treatment (combination of α- and β-adrenoreceptor antagonist and diuretics). Moreover, selective blockade of endothelin (ET) receptor type A (ET(A)) improved survival rate and attenuated hypertension and organ damage in Ren-2 transgenic rats. Therefore, we were interested in whether ET(A) receptor blockade could have additive effects to the classical blockade of the RAS. Transgenic rats underwent 5/6 renal ablation at the age of 2 months and were treated for 20 weeks with RAS blockers alone (angiotensin II receptor blocker - losartan, and angiotensin-converting enzyme inhibitor - trandolapril), ET(A) receptor blocker alone (atrasentan) or with the combination of RAS and ET(A) receptor blockade. RAS blockade normalized blood pressure and improved survival. It decreased cardiac hypertrophy and proteinuria as well as tissue angiotensin II and ET-1 levels. In contrast, ET(A) receptor blockade only partially improved survival rate, reduced blood pressure, attenuated the development of cardiac hypertrophy and transiently reduced proteinuria. However, no additive cardio- and renoprotective effects of ET(A) and RAS blockade were noted at the end of the study.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrasentan; Disease Models, Animal; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Hypertension, Renal; Indoles; Kidney; Losartan; Male; Nephrectomy; Pyrrolidines; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Angiotensin, Type 1; Receptor, Endothelin A; Renal Insufficiency, Chronic; Renin-Angiotensin System; Survival Analysis; Treatment Outcome

Growing evidence suggests that active vitamin D slows the progression of chronic kidney diseases. Here we compared the individual renal protective efficacy of paricalcitol and trandolapril (an angiotensin-converting enzyme inhibitor) in obstructive nephropathy, and examined any potential additive effects of their combination on attenuating renal fibrosis and inflammation. Mice underwent unilateral ureteral obstruction and were treated individually with paricalcitol or trandolapril or their combination. Compared to vehicle-treated controls, monotherapy with paricalcitol or trandolapril inhibited the expression and accumulation of fibronectin and type I and type III collagen, suppressed alpha-smooth muscle actin, vimentin, and Snail1 expression, and reduced total collagen content in the obstructed kidney. Combination therapy led to a more profound inhibition of all parameters. Monotherapy also suppressed renal RANTES (regulated on activation, normal T cell expressed and secreted) and tumor necrosis factor (TNF)-alpha expression and inhibited renal infiltration of T cells and macrophages, whereas the combination had additive effects. Renin expression was induced in the fibrotic kidney and was augmented by trandolapril. Paricalcitol blocked renin induction in the absence or presence of trandolapril. Our study indicates that paricalcitol has renal protective effects, comparable to that of trandolapril, in reducing interstitial fibrosis and inflammation. Combination therapy had additive efficacy in retarding renal scar formation during obstructive nephropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Base Sequence; Basement Membrane; Chemokine CCL5; Collagen; DNA Primers; Drug Synergism; Drug Therapy, Combination; Ergocalciferols; Extracellular Matrix Proteins; Fibrosis; Gene Expression; Indoles; Macrophages; Male; Mice; Renal Insufficiency, Chronic; Renin; RNA, Messenger; Snail Family Transcription Factors; T-Lymphocytes; Transcription Factors; Tumor Necrosis Factor-alpha; Ureteral Obstruction; Vimentin