Novel mechanism of intra-renal angiotensin II-induced sodium/proton exchanger 3 expression by losartan in spontaneously hypertensive rats

Abstract

The present study aimed to investigate the molecular pharmacodynamic mechanisms of losartan used in the treatment of hypertension. A total of 12 spontaneously hypertensive rats (SHR) were divided randomly into an SHR group treated with saline and LOS group treated with losartan. Six Wistar‑kyoto rats (WKY) were enrolled as the WKY group with saline in the study. The LOS group received 30 mg/kg/day losartan by intragastric injection, while the SHR and WKY were fed the same volume of saline. The dosage was modulated according to the weekly weight. Changes in blood pressure were measured by the indirect tail cuff method. Angiotensin (Ang) II production in the plasma and renal tissue was measured by an immunoradiometric method. Na+/H+ exchanger (NHE)3 and serum and glucocorticoid‑inducible kinase (SGK)1 were assessed by quantitative polymerase chain reaction (qPCR) and western blot analysis. When compared with the WKY group, the blood pressure of the SHR and LOS groups were higher prior to treatment with losartan. Following two weeks, blood pressure was reduced and the trend continued to decrease over the following six weeks. The plasma and renal tissue levels of Ang II in the SHR and LOS groups were significantly higher than those in the WKY group. NHE3 and SGK1 were increased at the mRNA and protein level in the SHR group, and losartan reduced the expression of both of them. The results suggested that in hypertensive rats, the circular and tissue renin angiotensin systems were activated, and the increased Ang II stimulated the expression of NHE3 and SGK1, which was reduced by losartan. Therefore, the effects of losartan in hypertension may be associated with the Ang II‑SGK1‑NHE3 of intra‑renal tissue.

Gallic Acid Reduces Blood Pressure and Attenuates Oxidative Stress and Cardiac Hypertrophy in Spontaneously Hypertensive Rats

“…3D ). It has been reported to increase angiotensin II concentration in the blood plasma of SHRs 38 , 39 . We sought to determine whether the increased transcription factor levels in SHR hearts could be observed in angiotensin II-treated H9c2 cells.…”

Olive leaf extract attenuates adriamycin‐induced focal segmental glomerulosclerosis in spontaneously hypertensive rats via suppression of oxidative stress, hyperlipidemia, and fibrosis

“…The renin angiotensin system (RAS) is a potent PAI-1 inducer, and a direct link among angiotensin II, PAI-1, and fibrosis without dependence on TGF-β as a mediator, was shown in the experimental model of renal fibrosis (Ma & Fogo, 2016). The level of angiotensin II is increased in SHR (Fan et al, 2014), thus we suggest that increased fibronectin level in the kidney of SHR with ADR-induced FSGS could be at least in part mediated by RAS induction of PAI-1, independently of TGF-β.…”

20-Hydroxyeicosatetraenoic Acid (HETE)-dependent Hypertension in Human Cytochrome P450 (CYP) 4A11 Transgenic Mice

“…However, ANGII has been reported to induce SGK1 expression in cultured human and mouse fibroblasts (41,42) and in primary cultures of human proximal tubule cells (43). Moreover, the ATR1 antagonist losartan lowers plasma and renal ANGII levels and renal SGK1 expression in spontaneously hypertensive rats (44). Based on these observations, we examined whether renal SGK1 mRNA and protein expression are elevated in B-129/Sv-4A11 ϩ/ϩ mice relative to wild-type controls.…”