The role of Sigma-1 receptor in sex-specific heat shock response in an experimental rat model of renal ischaemia/reperfusion injury

Abstract

We previously showed that female rats are more protected against renal ischaemia/reperfusion (I/R) injury than males, which is partly attributed to their more pronounced heat shock response. We recently described that Sigma-1 receptor (S1R) activation improves postischaemic survival and renal function. 17β-estradiol activates S1R, thus here we investigated the role of sex-specific S1R activation and heat shock response in severe renal I/R injury. Proximal tubular cells were treated with 17β-estradiol, which caused direct S1R activation and subsequent induction of heat shock response. Uninephrectomized female, male and ovariectomized female (Ovx) Wistar rats were subjected to 50-min renal ischaemia followed by 2 (T2) and 24 (T24) hours of reperfusion. At T24 renal functional, impairment was less severe and structural damage was less prominent in females versus males or Ovx. Postischaemic increase in S1R, pAkt, HSF-1, HSP72 levels were detected as early as at T2, while pHSP27 was elevated later at T24. Abundance of heat shock proteins was higher in healthy female rats and remained higher at T2 and T24 (female versus male or Ovx; resp.). We propose a S1R-dependent mechanism, which contributes to the relative renoprotection of females after I/R injury by enhancing the heat shock response.

The Selective Estrogen Receptor Modulator, Raloxifene, Is Protective Against Renal Ischemia–reperfusion Injury

“…21 We and other groups have demonstrated the protective role of supplemental 17β-estradiol in animal models of renal IRI, and we have demonstrated that the presence of ERα is necessary for the improved renal IRI tolerance observed among female mice as well as the protective effect of supplemental 17β-estradiol. 1,[5][6][7][8]22,23 Additionally, estrogen has also been investigated in cardiovascular disease and cardiac IRI 7,21 ; however, large clinical studies have raised concerns that estrogen therapy may increase the risk of heart disease, venous thromboembolism, stroke, and breast cancer. 13,14 SERMs are a broad class of drugs with a variety of different tissue-specific agonist/antagonist effects on the estrogen receptor, and there is little knowledge of the effects of SERMs on renal IRI.…”

“…[1][2][3][4] Although the exact mechanism is not yet known, estrogen appears to exert its protective effects by ameliorating ischemia-reperfusion injury (IRI). 1,[5][6][7][8] In renal transplantation IRI results in delayed graft function (DGF), defined as requiring dialysis in the first week after transplantation. 9 DGF results in increased costs, length of stay, readmissions after transplantation, rejection, and graft failure.…”

Animal Models of Renal Pathophysiology and Disease

“…Not only the outcome of AKI is better in females [22,23], but the progression of renal function deterioration during the aging process [24] as well as other chronic renal diseases [25] is also slower in females compared to males. Some studies support the protective role of female hormones (17β-estradiol, progesterone) [26][27][28]. Others highlight the negative effect of testosterone: Park et al found more severe renal injury after testosterone therapy in female, ovariectomized, and castrated male mice [29].…”

Recent advances in drug discovery efforts targeting the sigma 1 receptor system: Implications for novel medications designed to reduce excessive drug and food seeking

“…Finally, although there are some examples of studies examining behavioral outcomes in both male and female animals, potential sex-dependent effects of S1R antagonists remain to be fully characterized. This is important, as S1R is activated by 17b-estradiol and testosterone, which bind at different sites and can exert opposing pharmacological effects [ 116 , 117 ] and sex-dependent effects of S1R antagonists on other health-related outcomes have been reported in rats [ 117 ].…”