title: Irreversible renal damage after transient renin-angiotensin system stimulation: involvement of an AT1-receptor mediated immune response.
abstract: Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-Ren2 transgenic rats. In our current study we hypothesized that activation of the AT1-receptor (AT1R) leads to a T-cell response causing irreversible impairment of renal function and hypertension. Cyp1a1-Ren2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C). Rats were fed a I3C diet between 4-8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4-8 weeks. Rats were placed for 24h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. The development of sustained hypertension was completely prevented by losartan, whereas hydralazine only caused a partial decrease in BP. Markers of renal damage: KIM-1 and osteopontin were highly expressed in urine and kidney samples of I3C-treated rats, even until 20 weeks of age. Additionally, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas the expression of T-helper 1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes. In young Cyp1a1-Ren2 rats AT1R activation leads to induction of an immune response, causing a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension.
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. bart.heijnen@maastrichtuniversity.nl
authors.forename: Bart F J
authors.initials: BF
authors.lastname: Heijnen
authors.forename: Jelly
authors.initials: J
authors.lastname: Nelissen
authors.forename: Helma
authors.initials: H
authors.lastname: van Essen
authors.forename: Gregorio E
authors.initials: GE
authors.lastname: Fazzi
authors.forename: Jan W
authors.initials: JW
authors.lastname: Cohen Tervaert
authors.forename: Carine J
authors.initials: CJ
authors.lastname: Peutz-Kootstra
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.forename: Ben J A
authors.initials: BJ
authors.lastname: Janssen
authors.forename: Harry A J
authors.initials: HA
authors.lastname: Struijker-Boudier
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology; D051381:Rats; D055647:Rats, Transgenic; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D044140:Receptor, Angiotensin, Type 1; D006830:Hydralazine; D019808:Losartan