Combination therapy with paricalcitol and trandolapril reduces renal fibrosis in obstructive nephropathy.
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.
Tan
Xiaoyue
X
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
He
Weichun
W
Liu
Youhua
Y
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000818:Animals; D001483:Base Sequence; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004872:Ergocalciferols / Q000008:administration & dosage*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012083:Renin / Q000235:genetics; D000071250:Snail Family Transcription Factors; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014746:Vimentin / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D017931:DNA Primers; D004872:Ergocalciferols; D016326:Extracellular Matrix Proteins; D007211:Indoles; D012333:RNA, Messenger; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; C052035:trandolapril; C084656:paricalcitol; D003094:Collagen; D012083:Renin