title: Specific MAP-kinase blockade protects against renal damage in homozygous TGR(mRen2)27 rats.
abstract: Angiotensin II (AngII) plays an important role in renal damage by acting on hemodynamics, cell-growth, proliferation, and fibrosis, mainly by effects on the AngII type 1 (AT(1)) receptor. The AT(1) receptor activates several intracellular signaling molecules such as mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and p38, but their role in AngII-mediated renal damage is not well characterized. We therefore investigated whether pharmacologic blockade of ERK and p38 could prevent renal damage in high-renin homozygous transgenic rats (Ren2), with the effects of an AT(1) receptor antagonist (AT(1)-RA) as a reference. Seven-week-old homozygous Ren2 rats were treated with low-dose AT(1)-RA candesartan, ERK inhibitor tyrphostin, or p38 inhibitor SB239063 for 4 weeks. Untreated Ren2 and SD rats served as controls. Blood pressure was measured at 7 and 11 weeks. At 11 weeks, plasma renin activity (PRA) and serum aldosterone were determined, and the animals were killed. Kidney sections were scored for glomerular and interstitial smooth muscle actin and glomerular desmin expression as early markers for renal damage. Mesangial matrix expansion was determined as a marker for structural damage. PRA and aldosterone levels were elevated in untreated Ren2 rats in comparison to SD controls. AT(1)-RA further increased PRA but decreased aldosterone. All parameters of renal damage were elevated in untreated Ren2 rats. Blood pressure was not elevated at week 7 in Ren2 and not affected by either treatment. Mild signs of hypertensive damage were found in untreated Ren2 rats. All interventions significantly diminished damage to glomerular epithelium and interstitium. In addition, AT(1) receptor and p38 blockade reduced mesangial matrix expansion. In homozygous Ren2 rats, renal damage was ameliorated by a nonhypotensive dose of an AT(1)-RA and, similarly, by blockade of ERK or p38. This suggests that ERK and p38 are involved in AngII-mediated renal damage.
authors.affiliation: Departments of Pathology and Laboratory Medicine, University Hospital Groningen, Groningen, the Netherlands. m.h.de.borst@path.azg.nl
authors.forename: Martin H
authors.initials: MH
authors.lastname: de Borst
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.forename: Sippie
authors.initials: S
authors.lastname: Huitema
authors.forename: Lotte M
authors.initials: LM
authors.lastname: Vis
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
mesh_terms: D000199:Actins / Q000378:metabolism; D000450:Aldosterone / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D030801:Animals, Genetically Modified; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D003893:Desmin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006720:Homozygote; D007093:Imidazoles / Q000494:pharmacology; D007674:Kidney Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D020032:Tyrphostins / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D003893:Desmin; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D013777:Tetrazoles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020032:Tyrphostins; D000450:Aldosterone; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D012083:Renin; C406525:SB 239063; C081643:candesartan