Abstract
To investigate the effects of the transient receptor potential vanilloid type 1 (TRPV1) channel on renal extracellular matrix (ECM) protein expression including collagen deposition and the transforming growth factor β (TGF-β)/Smad signaling pathway during salt-dependent hypertension, wild-type (WT) and TRPV1-null (TRPV1⁻/⁻) mutant mice were uninephrectomized and given deoxycorticosterone acetate (DOCA)-salt for 4 wks. TRPV1 gene ablation exaggerated DOCA-salt-induced impairment of renal function as evidenced by increased albumin excretion (μg/24 h) compared with WT mice (83.7 ± 7.1 versus 28.3 ± 4.8, P < 0.05), but had no apparent effect on mean arterial pressure (mmHg) as determined by radiotelemetry (141 ± 4 versus 138 ± 3, P > 0.05). Morphological analysis showed that DOCA-salt-induced glomerulosclerosis, tubular injury and macrophage infiltration (cells/mm²) were increased in TRPV1⁻/⁻ compared with WT mice (0.74 ± 0.08 versus 0.34 ± 0.04; 3.14 ± 0.26 versus 2.00 ± 0.31; 68 ± 5 versus 40 ± 4, P < 0.05). Immunostaining studies showed that DOCA-salt treatment decreased nephrin but increased collagen type I and IV as well as phosphorylated Smad2/3 staining in kidneys of TRPV1⁻/⁻ compared with WT mice. Hydroxyproline assay and Western blot showed that DOCA-salt treatment increased collagen content (μg/mg dry tissue) and fibronectin protein expression (%β-actin arbitrary units) in the kidney of TRPV1⁻/⁻ compared with WT mice (26.7 ± 2.7 versus 17.4 ± 1.8; 0.93 ± 0.07 versus 0.65 ± 0.08, P < 0.05). Acceleration of renal ECM protein deposition in DOCA-salt-treated TRPV1⁻/⁻ mice was accompanied by increased TGF-β1, as well as phosphorylation of Smad2/3 protein expression (%β-actin arbitrary units) compared with DOCA-salt-treated WT mice (0.61 ± 0.07 versus 0.32 ± 0.05; 0.57 ± 0.07 versus 0.25 ± 0.05; 0.71 ± 0.08 versus 0.40 ± 0.06, P < 0.05). These results show that exaggerated renal functional and structural injuries are accompanied by increased production of ECM protein and activation of the TGF-β/Smad2/3 signaling pathway. These data suggest that activation of TRPV1 attenuates the progression of renal fibrosis possibly via suppression of the TGF-β and its downstream regulatory signaling pathway.
Highlights
Hypertension is a leading risk factor contributing to the development and progression of chronic renal disease [1]
deoxycorticosterone acetate (DOCA)-salt treatment significantly increased the ratio of kidney to body weight in WT and TRPV1–/– mice compared with their respective control mice (P < 0.05), but no difference was found between DOCAsalt-treated WT and TRPV1–/– mice (P > 0.05)
DOCA-salt treatment resulted in a significant increase in urinary albumin excretion in WT and TRPV1–/– mice, with the excretion in TRPV1–/– mice being significantly greater than WT mice (P < 0.05)
Summary
Hypertension is a leading risk factor contributing to the development and progression of chronic renal disease [1]. Hypertension-induced renal injury displays several characteristics including proteinuria, inflammatory cell recruitment and accumulation of extracellular matrix (ECM) proteins in the glomerular and tubulointerstitial spaces [2,3]. The resulting glomerulosclerosis and tubulointerstitial fibrosis are believed to lead to progressive renal insufficiency. It has been demonstrated that increased ECM protein synthesis and/or decreased ECM degradation contributes to the development of renal glomerulosclerosis and tubulointerstitial fibrosis [3,4]. TGF-β plays a major role in the tissue response to injury by regulating both cellular proliferation and ECM turnover through the Smad signaling pathway [6,7]. TGF-β is highly expressed in injured tissues, and TGF-β-dependent effects play a role in the pathogenesis of atherosclerosis, coronary artery disease and hypertension [8,9,10,11]
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