title: Role of the monocyte chemoattractant protein-1/C-C chemokine receptor 2 signaling pathway in transient receptor potential vanilloid type 1 ablation-induced renal injury in salt-sensitive hypertension.
abstract: Our recent studies indicate that the transient receptor potential vanilloid type 1 (TRPV1) channel may act as a potential regulator of monocyte/macrophage recruitment to reduce renal injury in salt-sensitive hypertension. This study tests the hypothesis that deletion of TRPV1 exaggerates salt-sensitive hypertension-induced renal injury due to enhanced inflammatory responses via monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2)-dependent pathways. Wild type (WT) and TRPV1-null mutant (TRPV1(-/-)) mice were subjected to uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for four weeks with or without the selective CCR2 antagonist, RS504393. DOCA-salt treatment increased systolic blood pressure (SBP) to the same degree in both strains, but increased urinary excretion of albumin and 8-isoprostane and decreased creatinine clearance with greater magnitude in TRPV1(-/-) mice compared to WT mice. DOCA-salt treatment also caused renal glomerulosclerosis, tubulointerstitial injury, collagen deposition, monocyte/macrophage infiltration, proinflammatory cytokine and chemokine production, and NF-κB activation in greater degree in TRPV1(-/-) mice compared to WT mice. Blockade of the CCR2 with RS504393 (4 mg/kg/day) had no effect on SBP in DOCA-salt-treated WT or TRPV1(-/-) mice compared to their respective controls. However, treatment with RS504393 ameliorated renal dysfunction and morphological damage, and prevented the increase in monocyte/macrophage infiltration, cytokine/chemokine production, and NF-κB activity in both DOCA-salt hypertensive strains with a greater effect in DOCA-salt-treated TRPV1(-/-) mice compared to DOCA-salt-treated WT mice. No differences in CCR2 protein expression in kidney were found between DOCA-salt-treated WT and TRPV1(-/-) mice with or without RS504393 treatment. Our studies for the first time indicate that deletion of TRPV1 aggravated renal injury in salt-sensitive hypertension via enhancing MCP-1/CCR2 signaling-dependent inflammatory responses.
authors.affiliation: Central Laboratory and Division of Cardiology, First Affiliated Hospital, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China wangyp8@163.com.
authors.forename: Youping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Central Laboratory and Division of Cardiology, First Affiliated Hospital, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Central Laboratory and Division of Cardiology, First Affiliated Hospital, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cui
authors.affiliation: Central Laboratory and Division of Cardiology, First Affiliated Hospital, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Liu
authors.affiliation: Central Laboratory and Division of Cardiology, First Affiliated Hospital, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Central Laboratory and Division of Cardiology, First Affiliated Hospital, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China.
authors.forename: Si
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Donna H
authors.initials: DH
authors.lastname: Wang
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism*; D064791:Desoxycorticosterone Acetate / Q000008:administration & dosage; D006973:Hypertension / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013141:Spiro Compounds / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000172:deficiency* / Q000235:genetics
chemical_list: D048588:Benzoxazines; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C579117:RS 504393; D054390:Receptors, CCR2; D017673:Sodium Chloride, Dietary; D013141:Spiro Compounds; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D064791:Desoxycorticosterone Acetate
keywords: Transient receptor potential vanilloid type 1 channel; chemokine receptor 2; deoxycorticosterone acetate-salt hypertension; mice; renal injury