Abstract P432: CTRP1 Contributes To Angiotensin II-Induced Hypertension Via Activation Of Intrarenal Renin

Abstract

C1q/TNF-related protein 1(CTRP1) is generally regarded as an adipokine and its circulating level is elevated in patients with hypertension. However, the functional role and mechanism of CTRP1 in blood pressure (BP) regulation largely remains elusive. In the present study, we investigated the BP phenotype of global CTRP1 knockout mice (termed CTRP1 KO) during angiotensin II (AngII) infusion and further explored the underlying mechanism involving the intrarenal renin. At baseline, 4-mo-old CTRP1 KO mice exhibited no developmental abnormalities or had normal BPs as compared with wild-type controls (WT). AngII infusion (300 ng/min/kg) induced a 3-fold increase in plasma and urinary CTRP1 levels as assessed by ELISA, but it was undetectable in CTRP1 KO mice. By radiotelemetry, AngII-infused CTRP1 KO mice exhibited reduced MAP as compared with AngII-infused WT mice (MAP [mmHg] in Day 7: 124.1 ± 2.4 in CTRP1 KO mice vs. 135 ± 3.1 in WT mice, n = 4 for each group, p < 0.05 by Student’s t test). This reduction was accompanied by a diminished response in intrarenal renin expression, as evidenced by urinary total prorenin/renin excretion ([ng/24h]: 0.51 ± 0.08 in WT/Vehicle vs. 1.22 ± 0.12 in WT/AngII; 0.32 ± 0.11 in CTRP1 KO/Vehicle vs. 0.54 ± 0.09 in CTRP1 KO/AngII; p < 0.05 by Two-way ANOVA analysis) and renal medullary mRNA levels (qRT-PCR: 1.00 ± 0.18 in WT/Vehicle vs. 3.73 ± 0.59 in WT/AngII; 0.52 ± 0.21 in CTRP1 KO/Vehicle vs. 1.31 ± 0.37 in CTRP1 KO/AngII, p < 0.05 by Two-way ANOVA analysis). In contrast, renal cortical renin mRNA was suppressed by AngII infusion more significantly in WT than in CTRP1 KO mice. In cultured mouse collecting duct-derived M-1 cells, treatment with recombinant human CTRP1-His protein (hCTRP1-His) at 20 nM for 24 hours consistently upregulated renin expression at both protein (Densitometry: 1.00 ± 0.23 in Vehicle group vs. 2.58 ± 0.42 in hCTRP1-His group, p < 0.05) and mRNA levels (qRT-PCR: 1.00 ± 0.12 in Vehicle group vs. 11.60 ± 1.21 in hCTRP1-His group, p < 0.05) levels. Collectively, these findings provide evidence favoring CTRP1 as a regulator of intrarenal renin mediating AngII-induced hypertension and further suggest CTRP1 as a potential mediator of adipose-renal crosstalk.