The renal transcriptome in experimental hypertension

Abstract

The renal transcriptome in experimental hypertension The kidneys importantly determine blood pressure. Kidney dysfunction can result in hypertension, which in turn leads to renal damage. In primary hypertension the cause is unknown. The condition is polygenic, however, which genetic defects cause elevated blood pressure remains obscure. Models of secondary hypertension have a known mono-causal pathogenesis. This thesis addresses primary and secondary hypertension in rats and mice and focuses on the renal cortical transcriptome (studied using microarrays) in relation to blood pressure. Three studies were performed on transcription modulation in spontaneously hypertensive rats (SHR), a rat model for primary hypertension. First, renal cortical transcription was studied from newborn to old SHR and compared to normotensive Wistar-Kyoto rats of the same ages. A number of persistent changes in renal gene expression was observed in SHR, but also a remarkable switch in the direction of altered expression of some genes in early life. Second, adult SHR were treated with several antihypertensive regimens. Mono-therapy with antihypertensive agents failed to normalize blood pressure. Angiotensin II (Ang II) AT1 receptor blocker, calcium channel inhibitor and two agents inhibiting oxidative stress caused quite distinct modulation of the renal cortical transcriptome. As a consequence, in the third study it was tested whether combining antihypertensive treatments led to a further decrease in blood pressure and to normalization of the renal cortical transcriptome in SHR towards WKY. This was indeed the case. Epoxide hydrolase 2 (Ephx2) that metabolizes the vasodilator epoxyeicosatrienoic acid, was consistently induced in renal cortex of SHR at all ages. Yet up till now Ephx2 has not been recognized as “hypertensive” gene in the rat because it does not lie within a so-called quantitative trait locus (QTL) for blood pressure. This illustrates the limitation of the QTL approach that by definition is determined by measurements of blood pressure. This is impossible in newborn and pre-weaning pups. Inhibiting Ephx2 in SHR during pregnancy and up to 4 weeks after birth revealed persistently lower blood pressure in female SHR up to 28 weeks of age compared to untreated SHR. In studies on secondary hypertension the vasoconstrictor Ang II was infused or synthesis of the vasodilator nitric oxide (NO) was inhibited for several weeks in wild-type mice or rats, respectively. Both treatments caused hypertension, however, renal damage only occurred in NO-depleted rats. The transcriptome in damaged and non-damaged kidneys did not reveal many candidates related to potentially damaging effects of Ang II or NO depletion, but rather revealed reduced synthesis of the protective antioxidants glutathione and bilirubin even before onset of renal damage. The thesis indicates the usefulness of genomics to study renal processes in genetic models of hypertension, both before onset of hypertension and when hypertension is manifest. Moreover, antihypertensive treatment responses in the kidneys were successfully analyzed. The studies underline the importance of antioxidants in renal protection against damaging effects of hypertension and suggest that combining antihypertensive agents not only further reduces blood pressure and the risk of end-organ damage but also lead to further normalization of the renal transcriptome.