Stimulation of Sigma-1 receptor by dehydroepiandrosterone ameliorates hypertension-induced kidney hypertrophy in ovariectomized rats

Abstract

The incidence of chronic renal disease in women increases with aging, especially after menopause, suggesting that loss of sex hormones contributes to the development and progression of renal diseases. Recent studies revealed that decreased dehydroepiandrosterone (DHEA) levels are associated with endothelial dysfunction, renal injury and increased cardiovascular mortality in postmenopausal women. We here investigate the role of DHEA, also known as Sigma-1 receptor (Sigma-1R) agonist, on kidney injury induced by pressure overload (PO) after ovariectomy (OVX) and defined mechanisms underlying its protective action. Wistar rats subjected to bilateral OVX were further treated with abdominal aortic stenosis between the right and left renal arteries. DHEA (15 and 30 mg/kg) was administered orally once a day for 14 days starting from two weeks after aortic banding. Time course study indicated that the right kidney (RK) weight-to-body weight (BW) ratio increases time-dependently from one to four weeks along with increased mean arterial blood pressure (MABP) after banding in the abdominal aorta with no change in the left kidney (LK) weight-to-BW ratio. Similarly, we found significant time-dependent decrease in Sigma-1R expression in the RK with no changes in the LK. Administration of the Sigma-1R agonist, DHEA, significantly inhibited hypertension-induced increases in the RKW-to-BW ratio and increased expression of Sigma-1R in the RK. DHEA also attenuated PO-induced disturbance of heart rate and MABP. DHEA administration significantly restored PO-induced impaired endothelial nitric oxide synthase (eNOS) activity with concomitant increased phosphorylation of eNOS (Ser1179) and Akt activity with increased phosphorylation at Ser 473 and at Thr 308 in the RK. We here documented, for the first time, the potential role of Sigma-1R to protect the kidney from PO-induced injury in ovariectomized rats. DHEA administration protects hypertension-induced kidney injury via upregulation of Sigma-1R and stimulation of Akt-eNOS signaling in ovariectomized rats.

Efeitos do deidroepiandrosterona (DHEA) sobre a função vascular e a resistência periférica à insulina em um modelo experimental de menopausa.

“…In line with the present results obtained in aorta, Bhuiyan & Fukunaga (2010) showed a decrease in eNOS phosphorylation in kidney from ovariectomized Wistar rats. Moreover, Widder et al (2003) demonstrated that ovariectomy is related to a reduction of eNOS protein expression in aorta from SHR rats, which was not observed in our study using aorta from Wistar rats.…”

“…It may reduce cardiac fibrosis in diabetic rats (Aragno et al 2008), delay atherosclerotic plaque formation in rabbits (Hayashi et al 2000), reduce weight gain and fat deposition in rats (Han et al 1998), increase insulin sensitivity (Campbell et al 2004) and insulin secretion in rats (Medina et al 2006), and reduce blood pressure in ovariectomized rats (Bhuiyan & Fukunaga, 2010). In addition, DHEA increases in vitro endothelial proliferation (Williams et al 2004), and protects endothelial cells against apoptosis , both effects independently of oestrogen receptors.…”

Protective cardiovascular and renal actions of vitamin D and estrogen

“…The precursors for estrogens are the androgenic hormones testosterone and DHEA and low DHEA levels were reported to be associated with endothelial dysfunction, renal injury and increased cardiovascular mortality, thereby providing a rationale for DHEA supplementation in postmenopausal women (120). Administration of DHEA to ovariectomized rats protected against hypertension-induced kidney injury via upregulation of the sigma-1R receptor and stimulation of Akt-eNOS signaling (121). …”

Distinct cardioprotective effects of 17β-estradiol and dehydroepiandrosterone on pressure overload–induced hypertrophy in ovariectomized female rats

“…To address their pathophysiological relevance, we previously documented R 1 receptor expression levels and signaling in the heart, 16,21,22 kidney, 23 and thoracic aorta. 24,25 We found that PO-induced cardiac hypertrophy in ovariectomized rats and mice significantly decreases R 1 receptor expression in the left ventricle with concomitant cardiac contractile dysfunction.…”