title: Combination therapy with an angiotensin-converting enzyme inhibitor and a vitamin D analog suppresses the progression of renal insufficiency in uremic rats.
abstract: Monotherapy with angiotensin-converting enzyme inhibitors has been shown to be beneficial in suppressing the progression of experimentally induced kidney diseases. Whether such therapy provides additional benefits when combined with vitamin D or an analog of vitamin D has not been established. Rats were made uremic by 5/6 nephrectomy and treated as follows: Uremic + vehicle (UC), uremic + enalapril (30 mg/L in drinking water; E), uremic + paricalcitol (19-nor; 0.8 microg/kg, three times a week), and uremic + enalapril + paricalcitol (E + 19-nor). A group of normal rats served as control (NC). BP was significantly elevated in the UC and 19-nor groups compared with the NC group but was indistinguishable from normal in the E and E + 19-nor groups. The decrease in creatinine clearance and the increase in the excretion of urinary protein that were observed in the UC group were ameliorated by the use of E alone or by E + 19-nor (P < 0.05 versus UC). The glomerulosclerotic index was significantly decreased in both the 19-nor (P < 0.01) and E + 19-nor groups (P < 0.01) compared with the UC group. Tubulointerstitial volume was significantly decreased in both the E (P < 0.05) and E + 19-nor groups (P < 0.01) compared with the UC group. Both macrophage infiltration (ED-1-positive cells) and production of the chemokine monocyte chemoattractant protein-1 were significantly blunted in E + 19-nor compared with E group. TGF-beta1 mRNA and protein expression were increased in the UC group (mRNA: 23.7-fold; protein: 29.1-fold versus NC). These increases were significantly blunted in the 19-nor group (mRNA: 7.1-fold; protein: 8.0-fold versus NC) and virtually normalized in the E + 19-nor group (protein: 0.8-fold versus NC). Phosphorylation of Smad2 was also elevated in the UC group (7.6-fold versus NC) but less so in the 19-nor-treated rats (5.5-fold versus NC). When rats were treated with E + 19-nor, the phosphorylation of Smad2 was normal (1.1-fold versus NC). Thus, 19-nor can suppress the progression of renal insufficiency via mediation of the TGF-beta signaling pathway, and this effect is amplified when BP is controlled via renin-angiotensin system blockade.
authors.affiliation: Renal Division, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Masahide
authors.initials: M
authors.lastname: Mizobuchi
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Morrissey
authors.forename: Jane L
authors.initials: JL
authors.lastname: Finch
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Martin
authors.forename: Helen
authors.initials: H
authors.lastname: Liapis
authors.forename: Tadao
authors.initials: T
authors.lastname: Akizawa
authors.forename: Eduardo
authors.initials: E
authors.lastname: Slatopolsky
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D018450:Disease Progression; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000494:pharmacology*; D004872:Ergocalciferols / Q000494:pharmacology*; D005260:Female; D008264:Macrophages / Q000473:pathology; D009392:Nephrectomy; D010281:Parathyroid Hormone / Q000097:blood; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014511:Uremia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D014807:Vitamin D / Q000031:analogs & derivatives
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004872:Ergocalciferols; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014807:Vitamin D; C084656:paricalcitol; D004656:Enalapril