Control of Ferroptosis and Acute Tubular Necrosis by Female Sex Hormones and Estrogen Derivatives

• Applicant: Professor Dr. Andreas Linkermann
• Subject Area: Nephrology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 522190184

It has been recognized for longer than 6 decades that female tissues are resistant to ischemia-reperfusion injury (IRI), but an underlying mechanism remains elusive. Research during the last ten years has provided accumulating evidence for ferroptosis to contribute to IRI of various organs. Here, we identify isolated kidney tubules to be partially resistant to ferroptosis, and our preliminary data further indicate cell death propagation during ferroptosis of isolated kidney tubules to be inhibited by female sex hormones, such as 17beta-estradiol and its metabolites. These observations led us to the central hypothesis that estradiol derivatives function as ferroptosis inhibitors in general. Here, we propose to investigate systematically and in detail i) the antiferroptotic potency of female sex hormones, ii) the associated changes in lipid and oxilipid profiles of kidney tubules and iii) the regeneration of peroxidzed estradiols by oxidoreductases such as ferroptosis suppressor protein 1 (FSP1) in cell free systems and in vivo. This unique experimental setup will allow us to conclude on the mechanisms of estradiol-mediated control of ferroptosis in acute tubular necrosis and acute kidney injury.

• DFG Programme: Research Grants