RGD Reference Report - Late angiotensin II receptor blockade in progressive rat mesangioproliferative glomerulonephritis: new insights into mechanisms. - Rat Genome Database

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Late angiotensin II receptor blockade in progressive rat mesangioproliferative glomerulonephritis: new insights into mechanisms.

Authors: Villa, L  Boor, P  Konieczny, A  Kunter, U  Van Roeyen, CR  Denecke, B  Gan, L  Neusser, MA  Cohen, CD  Eitner, F  Scholl, T  Ostendorf, T  Floege, J  Floege, J 
Citation: Villa L, etal., J Pathol. 2013 Apr;229(5):672-84. doi: 10.1002/path.4151. Epub 2013 Mar 5.
RGD ID: 7483632
Pubmed: PMID:23192593   (View Abstract at PubMed)
DOI: DOI:10.1002/path.4151   (Journal Full-text)

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-alpha and -beta as well as transforming growth factor-beta1. 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CCL20HumanIgA glomerulonephritis disease_progressionIEP  RGD 
CCR6HumanIgA glomerulonephritis disease_progressionIEP  RGD 
Ccl20RatIgA glomerulonephritis disease_progressionISOCCL20 (Homo sapiens) RGD 
Ccl20MouseIgA glomerulonephritis disease_progressionISOCCL20 (Homo sapiens) RGD 
Ccr6RatIgA glomerulonephritis disease_progressionISOCCR6 (Homo sapiens) RGD 
Ccr6MouseIgA glomerulonephritis disease_progressionISOCCR6 (Homo sapiens) RGD 
CCR6Humanmembranoproliferative glomerulonephritis treatmentISOCcr6 (Rattus norvegicus) RGD 
Ccr6Ratmembranoproliferative glomerulonephritis treatmentIEP  RGD 
Ccr6Mousemembranoproliferative glomerulonephritis treatmentISOCcr6 (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccl20  (C-C motif chemokine ligand 20)
Ccr6  (C-C motif chemokine receptor 6)

Genes (Mus musculus)
Ccl20  (C-C motif chemokine ligand 20)
Ccr6  (C-C motif chemokine receptor 6)

Genes (Homo sapiens)
CCL20  (C-C motif chemokine ligand 20)
CCR6  (C-C motif chemokine receptor 6)


Additional Information