Specific MAP-Kinase Blockade Protects against Renal Damage in Homozygous TGR(mRen2)27 Rats

Martin H. De Borst*, Gerjan Navis, Rudolf A. De Boer, Sippie Huitema, Lotte M. Vis, Wiek H. Van Gilst, Harry Van Goor

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

30 Citations (Scopus)

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 (AT1) receptor. The AT1 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 AT1 receptor antagonist (AT1-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. AT1-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, AT1 receptor and p38 blockade reduced mesangial matrix expansion. In homozygous Ren2 rats, renal damage was ameliorated by a nonhypotensive dose of an AT1-RA and, similarly, by blockade of ERK or p38. This suggests that ERK and p38 are involved in AngII-mediated renal damage.

Original languageEnglish
Pages (from-to)1761-1770
Number of pages10
JournalLaboratory Investigation
Volume83
Issue number12
DOIs
Publication statusPublished - Dec 2003
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by a grant from the Groningen University Institute for Drug Exploration (GUIDE). Address reprint requests to: Dr. Martin H. de Borst, Department of Pathology and Laboratory Medicine, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. E-mail: m.h.de.borst@path.azg.nl

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