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.