T-cell profile and Treg regulation by angiotensin II type 2 receptor in acute kidney injury in male versus female rats

Sex differences have been suggested in acute kidney injury (AKI), a condition characterized by immune cell infiltration, including T cells. We recently reported that angiotensin type 2 receptor (AT 2 R) activation reduces immune (CD45 + ), T (CD3 + ), and helper T cells (CD4 + ), while increasing anti-inflammatory Treg cells (CD4 + FoxP3 + ) during ischemia-reperfusion (IR) AKI in the kidney. To understand sex differences, male, female, and ovariectomized (OVX) Sprague-Dawley rats were subjected to IR with or without the AT 2 R agonist C21. Kidneys and blood were collected three days after reperfusion. Females exhibited less tubular damage than males, which was attenuated by C21 and enhanced by ovariectomy. OVX rats showed reduced basal circulating Tregs and CD4 + AT 2 R + cells, which returned to normal post-IR. Males displayed higher basal CD45 + , CD3 + , and CD4 + cell levels compared to females; however, IR-induced increases and C21-mediated reduction in these immune cells accumulation was independent of sex. Tregs in the kidney remained higher in females, which was affected by OVX. The proportion of renal accumulation of Tregs-AT 2 R + (50% of the CD4 + ) greatly exceeds the kidney CD4 + AT 2 R + cells (~ 30% of CD4 + ). Overall, kidney injury and Tregs accumulation following IR were sex-dependent, which are influenced by ovarian hormonal status (OVX) and the AT 2 R-mediated reprotection and reduction in immune cells accumulation was an independent phenomenon.