title: Antihypertensive therapy induces compartment-specific chemokine expression and a Th1 immune response in the clipped kidney of Goldblatt hypertensive rats.
abstract: The present study examined the pathogenesis of interstitial inflammation and fibrosis in antihypertensively treated rats with two-kidney, one-clip hypertension. Hypertensive rats were randomized into four groups: no treatment and moderate, intermediate, and intensified lowering of blood pressure with increasing doses of a vasopeptidase inhibitor for 6 wk. The vasopeptidase inhibitor dose dependently lowered blood pressure. The tubulointerstitial damage was accompanied by a diffuse infiltration of mononuclear cells and circumscript mononuclear inflammatory cell cluster formation consisting mainly of T cells and to a lesser degree of macrophages and B cells. Real-time PCR analyses showed a dose-dependent induction of MCP-1 and the Th1-type chemokines IP10 and Mig as well as their receptor CXCR3 and the Th1 cytokine IFN-gamma. In situ hybridization and laser microdissection revealed a strong expression of these Th1-associated transcripts in the clusters and, in the case of MCP-1, also diffusely in the interstitium. The inflammation was accompanied by the appearance of myofibroblasts and synthesis of the fibrogenic factor plasminogen activator inhibitor-1 as well as the collagenase matrix metalloproteinase-2, leading to collagen I upregulation and interstitial scarring. No inflammation or fibrosis was found in normotensive rats treated with the vasopeptidase inhibitor. The renal injury in the clipped kidney is accompanied by compartment-specific chemokine expression and cell cluster formation of Th1 specificity associated with upregulation of fibrogenic proteins and matrix metalloproteinases. These findings suggest that the Th1 chemokines IP10 and Mig as well as their receptor CXCR3 are potential targets for therapeutic interventions in ischemic nephropathy.
authors.affiliation: Dept. of Medicine, Division of Nephrology, University Hospital of Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: O M
authors.initials: OM
authors.lastname: Steinmetz
authors.forename: S
authors.initials: S
authors.lastname: Sadaghiani
authors.forename: U
authors.initials: U
authors.lastname: Panzer
authors.forename: C
authors.initials: C
authors.lastname: Krebs
authors.forename: C
authors.initials: C
authors.lastname: Meyer-Schwesinger
authors.forename: T
authors.initials: T
authors.lastname: Streichert
authors.forename: S
authors.initials: S
authors.lastname: Fehr
authors.forename: I
authors.initials: I
authors.lastname: Hamming
authors.forename: H
authors.initials: H
authors.lastname: van Goor
authors.forename: R A K
authors.initials: RA
authors.lastname: Stahl
authors.forename: U
authors.initials: U
authors.lastname: Wenzel
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines / Q000096:biosynthesis*; D019743:Chemokines, CXC / Q000096:biosynthesis; D003404:Creatinine / Q000097:blood; D005355:Fibrosis; D015870:Gene Expression; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use*; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D007668:Kidney / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D053495:Osteopontin / Q000096:biosynthesis; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000199:Actins; D000959:Antihypertensive Agents; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines; D019743:Chemokines, CXC; D003404:Creatinine; D006575:Heterocyclic Compounds, 3-Ring; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D020778:Matrix Metalloproteinase 2; D053495:Osteopontin; D017395:Plasminogen Activator Inhibitor 1; C479877:AVE 7688; C505723:CXCL9 protein, rat; C491766:Ccl2 protein, rat; C091326:Cxcl10 protein, rat; C506897:Spp1 protein, rat; C498862:Acta2 protein, rat