733 Differential transcriptomicS of indapamide and hydrochlorothiazide in SHR kidney

Abstract

Background: Indapamide (INDA) and hydrochlorothiazide (HCT) are antihypertensive diuretics but only indapamide was shown to prevent morbi/mortality. We and others have shown that they have distinct effects on vascular proliferation. Objective and methods: Our goal was to compare whole transcriptome in kidneys of SHR treated with IND, HCT and untreated controls (CTL) in order to unveil gene pathways resulting from these treatments. Eighteen male SHR rats received either vehicle, IND (0,24 mg/kg/d) or HCT (1,5 mg/kg/d) for 3 weeks and kidney transcriptomics analysis was performed using Affymetrix Rat Exon 1.0 ST. Results: 645 and 593 genes were differentially expressed by HCT and INDA compared to CTL. 218 genes were modulated by both drugs in the same direction. Among common genes, 3 Kallikreins displayed a significantly higher expression (KLK1 1,66 fold) while calpain 6 (CAPN6, 1,30 fold) exhibited a significantly lower expression by INDA compared to HCT compatible with the higher hypotensive and vasculoprotective effects of indapamide. We observed a differential effect on T2D susceptibility gene expression, including TCF7L2, compatible with a higher diabetogenic effect of HCT compared to INDA. Several genes modulated by HCT were found to be associated with pathways related to cancer, cell growth and proliferation while, on the contrary, the genes modulated by INDA treatment were associated to cell quiescence (lower ploidy). Conclusion: The data indicate that a possible difference between the 2 drugs could reside in their differential capacity to induce hypotensive and proliferative genes. Further studies are required to translate these observations to humans.