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Kidney Week

Abstract: SA-PO084

Immunomodulation and T Cell Infiltration in AKI Caused by Ischemia-Reperfusion (IR): Role of Sex Difference and Angiotensin II Type 2 Receptor (AT2R)

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Faisal, Tahmid, University of Houston, Houston, Texas, United States
  • Ali, Riyasat, University of Houston, Houston, Texas, United States
  • Hussain, Tahir, University of Houston, Houston, Texas, United States
Background

A greater renoprotection against injury in females compared to males has been suggested. However, the mechanism and factors responsible for this difference are unknown. Recently, we have reported that angiotensin AT2R activation (by its agonist compound C21) attenuates immune cells infiltration in the kidney and increases protective/reparatory regulatory T cells (CD4+-FoxP3+ Treg) accumulation in the IR kidney in male rats. Present study is designed to evaluate sex difference in immune cell infiltration and T cells profiles in the IR kidney and the signaling mechanism by which AT2R promotes Treg modulation.

Methods

Male, female (ovary intact, Ovi) and ovariectomized (Ovx) SD rats were divided into 3 groups- sham, IR, and IR+C21 (daily 0.3 mg/kg, i.p). After 30 mins ischemia and 3 days of reperfusion, kidneys were incised and digested to make kidney cell suspension for flow cytometry of immune cells. To understand the signaling pathway(s) associated with AT2R mediated modulation of CD4 T cells into Treg cells, primary splenic CD4 T cells were cultured, induced Treg formation with pharmacological agents.

Results

Flow cytometry revealed that CD45 cells accumulation was increased in the IR kidney, being 2-fold higher in males than Ovi. The AT2R agonist C21 treatment reduced CD45 in both males and females equally. Preliminary studies show Ovx did not affect CD45 compared with Ovi but attenuated the response of the AT2R activation on CD45 cell reduction. Like CD45, basal CD3 and CD4 were higher in males than in Ovi , but these cells were similar in the IR groups and reduced by C21 treatment. Treg cells were higher in male than Ovi in IR and C21.There is an increasing pattern of AT2+Tregs cells in IR rats of all groups with 50% cells with AT2R expression. Normal blood CD3, CD4, CD4+AT2+T and Tregs cells did not show sex difference. Kidney injury markers showed less injury in IR Ovi females than males. Ex vivo studies show AT2R activation by C21 in splenic T cells modulation to Tregs is inhibited totally by the PP2A inhibitor okadaic acid and only partially by NO synthase inhibitor L-NAME.

Conclusion

Under AKI, there are fewer immune cells, including T cells accumulation in females compared to males and AT2R function is reduced by Ovx in females, suggesting a sex difference. AT2R modulates Tregs via PP2A pathway.

Funding

  • Other NIH Support