Candesartan-induced gene expression in five organs of stroke-prone spontaneously hypertensive rats.

To test the functional consequences of blocking the local renin-angiotensin system (RAS), we investigated the effects of an angiotensin II type 1 receptor blocker (ARB), candesartan, on the systemic gene expression profile of five important organs (brain, heart, kidney, liver and adipose tissues) in the stroke-prone spontaneously hypertensive rat (SHRSP), an established model of essential hypertension and cardiovascular disorders, and its normotensive control, the Wistar Kyoto (WKY) rat. Rats were treated with candesartan (5 mg/kg/d) for 4 weeks from 12 to 16 weeks of age. DNA microarray technology was used to identify changes in gene expression. Four weeks of treatment with candesartan significantly lowered systolic blood pressure in male rats of both the SHRSP and the WKY strains (p<0.0005). Candesartan differentially modulated the gene expression profile in an organ-specific manner in male SHRSP; of the five organs tested, gene expression was most prominently altered in the hearts of SHRSP. In contrast, candesartan treatment exerted minimal or no significant effects on the gene expression profile of the corresponding organs of male WKY rats. The inter-strain differences in gene expression changes induced by candesartan were considered to be associated with both blood pressure-dependent and independent mechanisms. These results help to delineate the mechanisms that underlie the organ or tissue protection conferred by ARB at the levels of cellular biology and genomics in the context of the local RAS. Further studies are warranted to investigate not only individual genes of interest but also genetic "networks" that involve differential organ- or tissue-specific gene expression induced by the blockade of RAS in essential hypertension. Tokyo, Japan