title: Late angiotensin II receptor blockade in progressive rat mesangioproliferative glomerulonephritis: new insights into mechanisms.
abstract: Mesangioproliferative glomerulonephritis is the most common nephritis worldwide. We examined the effects of low- and high-dose telmisartan, an angiotensin II receptor blocker, in rats with progressive anti-Thy1.1 mesangioproliferative glomerulonephritis in a clinically relevant situation of established renal damage. Uninephrectomized nephritic rats were randomized on day 28 to remain untreated (control treatment; CT), or to receive low- (0.1 mg/kg/day, LT) or high-dose telmisartan (10 mg/kg/day, HT), hydrochlorothiazide + hydralazine (8 + 32 mg/kg/day, HCT + H), or atenolol (100 mg/kg/day, AT). CT and LT rats were hypertensive, whereas HT, HCT + H and AT treatment normalized blood pressures. On day 131, despite similar blood lowering effects, only HT, but not AT or HCT + H, prevented loss of renal function and reduced proteinuria compared to CT. Only HT potently ameliorated glomerulosclerosis, tubulointerstitial damage, cortical matrix deposition, podocyte damage and macrophage infiltration. HT reduced cortical expression of platelet derived growth factor receptor-α and -β as well as transforming growth factor-β1. LT exhibited minor but significant efficacy even in the absence of antihypertensive effects. Transcript array analyses revealed a four-fold down-regulation of renal cortical chemokine (C-C motif) receptor 6 (CCR6) mRNA by HT, which was confirmed at the protein level. Silencing of CCR6 did not alter podocyte function in vitro, thus indicating a predominant role in the tubulo-interstitium. In human kidney biopsies, CCR6 mRNA and mRNA of its ligand chemokine (C-C motif) ligand 20 was up-regulated in patients with progressive IgA nephropathy compared to stable disease. Thus, delayed treatment with high-dose telmisartan exerted a pronounced benefit in progressive mesangioproliferative glomerulonephritis, which extended beyond that of equivalent blood pressure lowering. We identified down-regulation of platelet-derived growth factor receptors and CCR6 as potential mediators of telmisartan-related renoprotection. CCR6 may also regulate the renal outcome in human mesangioprolfierative glomerulonephritis.
authors.affiliation: Division of Nephrology, RWTH Aachen University Hospital, Germany. lvilla@ukaachen.de
authors.forename: Luigi
authors.initials: L
authors.lastname: Villa
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.forename: Andrzej
authors.initials: A
authors.lastname: Konieczny
authors.forename: Uta
authors.initials: U
authors.lastname: Kunter
authors.forename: Claudia R C
authors.initials: CR
authors.lastname: van Roeyen
authors.forename: Bernd
authors.initials: B
authors.lastname: Denecke
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Neusser
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Frank
authors.initials: F
authors.lastname: Eitner
authors.forename: Thomas
authors.initials: T
authors.lastname: Scholl
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001262:Atenolol / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D054337:Cell Dedifferentiation / Q000187:drug effects; D002460:Cell Line; D054418:Chemokine CCL20 / Q000235:genetics; D019610:Cytoprotection; D004195:Disease Models, Animal; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D006852:Hydrochlorothiazide / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007518:Isoantibodies; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009392:Nephrectomy; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D054399:Receptors, CCR6 / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000077333:Telmisartan; D013997:Time Factors; D014162:Transfection
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; C108355:CCL20 protein, human; C106311:CCR6 protein, human; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; D007518:Isoantibodies; D012333:RNA, Messenger; D054399:Receptors, CCR6; C035678:anti-Thy antibody; D006852:Hydrochlorothiazide; D006830:Hydralazine; D001262:Atenolol; D017479:Receptors, Platelet-Derived Growth Factor; D000077333:Telmisartan