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: Masahide Mizobuchi, Jeremiah Morrissey, Jane L Finch, Daniel R Martin, Helen Liapis, Tadao Akizawa, Eduardo Slatopolsky
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 18 Issue 6 Pg. 1796-806 (Jun 2007) ISSN: 1046-6673 [Print] United States
• PMID: 17513326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Ergocalciferols
• Parathyroid Hormone
• RNA, Messenger
• Transforming Growth Factor beta1
• Vitamin D
• paricalcitol
• Enalapril

Topics

• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Blood Pressure
• Disease Models, Animal
• Disease Progression
• Drug Therapy, Combination
• Enalapril (pharmacology)
• Ergocalciferols (pharmacology)
• Female
• Macrophages (pathology)
• Nephrectomy
• Parathyroid Hormone (blood)
• Proteinuria (drug therapy, pathology, physiopathology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Renal Insufficiency (drug therapy, pathology, physiopathology)
• Signal Transduction (physiology)
• Transforming Growth Factor beta1 (genetics, metabolism)
• Uremia (drug therapy, pathology, physiopathology)
• Vitamin D (analogs & derivatives)