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.