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Protective effect of TRPV1 against renal fibrosis via inhibition of TGF-beta/Smad signaling in DOCA-salt hypertension Wang Y; Wang DHMol Med 2011[]; 17 (11-12): 1204-12To 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 beta (TGF-beta)/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 (mug/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/mm(2)) 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 (mug/mg dry tissue) and fibronectin protein expression (%beta-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-beta1, as well as phosphorylation of Smad2/3 protein expression (%beta-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-beta/Smad2/3 signaling pathway. These data suggest that activation of TRPV1 attenuates the progression of renal fibrosis possibly via suppression of the TGF-beta and its downstream regulatory signaling pathway.|Animals[MESH]|Blood Pressure[MESH]|Desoxycorticosterone[MESH]|Fibronectins/metabolism[MESH]|Fibrosis[MESH]|Heart Rate[MESH]|Hypertension/chemically induced/complications/*pathology/physiopathology[MESH]|Kidney Cortex/metabolism/pathology/physiopathology[MESH]|Kidney Diseases/complications/metabolism/pathology/*prevention & control[MESH]|Kidney Glomerulus/metabolism/pathology/physiopathology[MESH]|Kidney/metabolism/*pathology/physiopathology[MESH]|Mice[MESH]|Phosphorylation[MESH]|Protective Agents/*metabolism[MESH]|Signal Transduction[MESH]|Smad Proteins/*metabolism[MESH]|Smad2 Protein/metabolism[MESH]|Smad3 Protein/metabolism[MESH]|TRPV Cation Channels/*metabolism[MESH]|Time Factors[MESH]|Transforming Growth Factor beta/*metabolism[MESH] |
