title: Effects and mechanisms of angiotensin II receptor blockade with telmisartan in a normotensive model of mesangioproliferative nephritis.
abstract: BACKGROUND
  Renoprotective actions of angiotensin receptor blockers are not well established in normotensive, low-grade proteinuric glomerular diseases. We examined the effect of low-dose telmisartan (LT) and high-dose telmisartan (HT) versus conventional antihypertensive therapy in the rat anti-Thy1.1 model of glomerulonephritis.
  
  
  METHODS
  Rats were randomized on Day 4 after disease induction to no treatment (CT, control), LT or HT or hydrochlorothiazide + hydralazine (HCT + H).
  
  
  RESULTS
  All rats remained normotensive: HT and HCT + H reduced blood pressure by 15-20%. LT, HT and HCT + H reduced glomerular endothelial cell proliferation and glomerular and interstitial matrix deposition on Day 14. Only HT reduced podocyte damage and tubular cell dedifferentiation on Day 9 and mesangial cell activation on Day 14. By gene expression analysis arrays, we identified discs-large homolog 1 and angiopoietin-like 4 as potential mediators of the HT effects. In addition, we identified several pathways possibly related to the pleiotropic effects of HT, including growth factor signalling, mammalian target of rapamycin signalling, protein ubiquitination, the Wnt-beta catenin pathway and hypoxia signaling.
  
  
  CONCLUSIONS
  In summary, treatment with HT, initiated after the induction of disease, ameliorates glomerular and tubulointerstitial damage. We provide the first comprehensive insight into the mechanisms underlying the renoprotective effect of high-dose angiotensin II receptor blockers (ARBs). Our study lays the basis for future investigations on novel pathways affected by ARBs in renal disease.
authors.affiliation: Division of Nephrology, University Hospital RWTH Aachen, Aachen, Germany. villaluigi@gmail.com
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: Michael B
authors.initials: MB
authors.lastname: Kupper
authors.forename: Kurt
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Frank
authors.initials: F
authors.lastname: Eitner
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 / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects; D008297:Male; D050527:Mesangial Cells / Q000166:cytology* / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011945:Receptors, Angiotensin / Q000737:chemistry* / Q000378:metabolism; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D015415:Biomarkers; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D000077333:Telmisartan