Document Detail


Late angiotensin II receptor blockade in progressive rat mesangioproliferative glomerulonephritis: new insights into mechanisms.
MedLine Citation:
PMID:  23192593     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Luigi Villa; Peter Boor; Andrzej Konieczny; Uta Kunter; Claudia R C van Roeyen; Bernd Denecke; Lin Gan; Matthias A Neusser; Clemens D Cohen; ; Frank Eitner; Thomas Scholl; Tammo Ostendorf; Jürgen Floege
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-03-05
Journal Detail:
Title:  The Journal of pathology     Volume:  229     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-05-02     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  672-84     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II Type 1 Receptor Blockers / administration & dosage,  pharmacology*
Animals
Antihypertensive Agents / administration & dosage,  pharmacology*
Atenolol / pharmacology
Benzimidazoles / administration & dosage,  pharmacology*
Benzoates / administration & dosage,  pharmacology*
Blood Pressure / drug effects
Cell Dedifferentiation / drug effects
Cell Line
Chemokine CCL20 / genetics
Cytoprotection
Disease Models, Animal
Fibrosis
Gene Expression Profiling
Gene Expression Regulation
Glomerular Mesangium / drug effects*,  metabolism,  pathology,  physiopathology
Glomerulonephritis, Membranoproliferative / drug therapy*,  etiology,  genetics,  metabolism,  pathology,  physiopathology
Humans
Hydralazine / pharmacology
Hydrochlorothiazide / pharmacology
Hypertension / drug therapy,  metabolism,  physiopathology
Inflammation / drug therapy,  metabolism,  physiopathology
Isoantibodies
Macrophages / drug effects,  metabolism,  pathology
Male
Mice
Nephrectomy
Podocytes / drug effects,  metabolism,  pathology
Proteinuria / drug therapy,  metabolism,  physiopathology
RNA Interference
RNA, Messenger / metabolism
Rats
Rats, Wistar
Receptors, CCR6 / genetics,  metabolism
Receptors, Platelet-Derived Growth Factor / drug effects,  genetics,  metabolism
Time Factors
Transfection
Chemical
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Antihypertensive Agents; 0/Benzimidazoles; 0/Benzoates; 0/CCL20 protein, human; 0/CCR6 protein, human; 0/CCR6 protein, mouse; 0/Chemokine CCL20; 0/Isoantibodies; 0/RNA, Messenger; 0/Receptors, CCR6; 0/anti-Thy antibody; 0J48LPH2TH/Hydrochlorothiazide; 26NAK24LS8/Hydralazine; 50VV3VW0TI/Atenolol; EC 2.7.10.1/Receptors, Platelet-Derived Growth Factor; U5SYW473RQ/telmisartan
Investigator
Investigator/Affiliation:
C D Cohen / ; H Schmid / ; M Fischereder / ; L Weber / ; M Kretzler / ; D Schlöndorff / ; J D Sraer / ; P Ronco / ; M P Rastaldi / ; G D'Amico / ; P Doran / ; H Brady / ; D Mönks / ; C Wanner / ; A J Rees / ; F Strutz / ; G A Müller / ; P Mertens / ; J Floege / ; N Braun / ; T Risler / ; L Gesualdo / ; F P Schena / ; J Gerth / ; G Wolf / ; R Oberbauer / ; D Kerjaschki / ; B Banas / ; B K Krämer / ; M Saleem / ; R P Wüthrich / ; W Samtleben / ; H Peters / ; H H Neumayer / ; M Daha / ; C Blume / ; B Grabensee / ; F Mampaso / ; J Oh / ; F Schaefer / ; M Zeier / ; H-J Gröne / ; P Gross / ; G Tonolo / ; V Tesar / ; H Rupprecht / ; H Pavenstädt / ; H-P Marti /

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