Irreversible Renal Damage after Transient Renin-Angiotensin System Stimulation: Involvement of an AT(1)-Receptor Mediated Immune Response

Bart F. J. Heijnen*, Jelly Nelissen, Helma van Essen, Gregorio E. Fazzi, Jan W. Cohen Tervaert, Carine J. Peutz-Kootstra, John J. Mullins, Casper G. Schalkwijk, Ben J. A. Janssen, Harry A. J. Struijker-Boudier

*Corresponding author for this work

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6 Citations (Web of Science)

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 AT(1)-receptor (AT(1)R) 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 Next, I3C was withdrawn and rats were followed-up for another 12 weeks.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 AT(1)R 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.
Original languageEnglish
Article numbere57815
JournalPLOS ONE
Volume8
Issue number2
DOIs
Publication statusPublished - 28 Feb 2013

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