704 IS THERE AN ESSENTIAL ROLE FOR ADAPTIVE IMMUNITY UNDERLYING RENIN-ANGIOTENSIN-INDUCED RENAL DAMAGE?

Abstract

Objective: Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-mRen2 transgenic rats. We hypothesize that activation of the AT1-receptor induces an adaptive immune response underlying this irreversible impairment of renal function and pathology. Methods: Cyp1a1-mRen2 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 Next, I3C was withdrawn and rats were followed-up for another 12 weeks.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 or hydralazine treatment between 4-8 weeks. Rats were placed for 24 h 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. Results: Losartan prevented the development of sustained hypertension, whereas hydralazine only caused a partial decrease in BP. KIM-1 and osteopontin, markers of renal damage linked to inflammation, were highly expressed in urine and kidney samples of I3C-treated rats, even till 20 weeks. Furthermore, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas expression of T-helper1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was ineffective. Conclusion: In young Cyp1a1-mRen2 rats AT1-receptor activation leads to induction of an adaptive immune response, a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension. This study was performed within the framework of TI-Pharma projectT2-301.