The effect of tamoxifen on gender differences in unilateral ureteral obstructed rats and human kidney slices

Abstract

BACKGROUNDRenal fibrosis is regarded as the most damaging process in chronic kidney disease (CKD) and it is the most consistent predictor of irreversible loss of renal function. To date, there is no good treatment for renal fibrosis. Interestingly, females are less prone to CKD, which might be due to estrogen. We have previously shown that tamoxifen (TAM), a selective estrogen receptor modulator, plays a role for regulation of renal water and salt balance. In this study, we will investigate the effect of tamoxifen on a well‐established in vivo model using unilateral ureteral obstruction (UUO)‐induced fibrosis in female, male and ovariectomized (OVX) female rats. Furthermore, a recently develop model of human renal fibrosis was used to study multicellular pathological processes in human tissue.METHODSFibrosis was induced by 7 days of UUO. Female OVX rats had both their ovaries removed two weeks before UUO. Tamoxifen (25 mg/kg for female rats and 50 mg/kg for male rats; a higher dose of tamoxifen was lethal for female rats) was given by oral gavage starting 5 days before UUO. Tamoxifen treatment was continued for 7 days after UUO. Human precision‐cut kidney slices were exposed to TGF‐β for 48h in order to make the tissue fibrotic and afterwards treated with tamoxifen for 6h. Histological changes were examined by HE staining. Expression of α‐smooth muscle actin, fibronectin, and TGF‐β were evaluated by immunohistochemistry, quantitative PCR, and western blot analysis.RESULTSRenal fibrosis was increased after UUO in both male, female and OVX rats. Tamoxifen treatment reduced fibronectin, α‐SMA and TGF‐β gene expression in female UUO rats, but not in male and in OVX rats subjected to UUO. Yet, tamoxifen significantly reduced the protein level of fibrotic markers and the kidney weight in response to UUO in both female as well as OVX and male rats. Furthermore, our data demonstrated that sham operated female and female OVX rats had a higher plasma creatinine level compared to male rats. On the other hand, TAM treated male rats subjected to UUO had a significantly increased urea plasma level, which was not observed in female and female OVX rats. Importantly, treatment with tamoxifen has a tendency to reduce fibronectin in human kidney slices exposed to TGF‐β from women but not in men.CONCLUSIONThese findings indicate that tamoxifen reduces UUO‐induced fibrosis in both female, female OVX and male rats, but have different effects on females and males when it comes to gene levels of fibrotic markers and plasma data. Furthermore, our finding provide preclinical evidence that treatment with tamoxifen affects men and women differently and the concentration of the drug must be adapted to the gender.Support or Funding InformationThis study was kindly supported by Karen Elise Jensen Foundation, the Danish Council for Independent Research, Aarhus University Foundation and the AP Møller Foundation.