Angiotensin II Type 2 Receptor (AT2R) Modulates CD4+ T Cells into Regulatory T Cells (Tregs) in Kidney Ischemia-Reperfusion Injury in Rats: Role of PP2A
- AKI: Mechanisms - III
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Faisal, Tahmid, University of Houston System, Houston, Texas, United States
- Ali, Riyasat, University of Houston System, Houston, Texas, United States
- Hussain, Tahir, University of Houston System, Houston, Texas, United States
Kidney ischemia reperfusion injury (IR) is the common pathophysiology of acute kidney injury (AKI) associated with immune cell infiltration including T cells. Male kidney is more susceptible to AKI than females. Recently, we have shown that IR causes infiltration of CD45+T cells in male rats and AT2R activation reduced renal CD45+ T cells infiltration and modulated CD4+T cells into anti-inflammatory Tregs ameliorating AKI. Infiltration of these cells in females and the mechanism of AT2R-mediated modulation of CD4T cells into Tregs are unknown.
Bilateral IR was performed on female SD rats for 30 mins. The rats were divided into 3 groups: sham,IR, and IR+C21 (AT2R agonist, i.p. 0.3 mg/kg b.wt). After 3 days kidney cells were isolated and analyzed with flow cytometry for investigating CD45+, CD3+, CD4+, and FoxP3+ Treg cells. Also B6 mouse splenic CD4+T cells were isolated using magnetically labelled anti-CD4, which were activated with anti-CD3/anti-CD28/ IL2/ TGFβ and treated with C21 alone or in the presence of AT2R antagonist PD123319, NO synthase inhibitor LNAME, PP2A inhibitor okadaic acid.
The female rats showed CD45+, CD3+ and CD4+ T cells infiltration 3days after IR. However, the renal accumulation of CD45 and Tregs is lower in female (<1% of total kidney cells) compared to 3 days IR data in male (7%) rats- suggesting a sex difference. C21 administration reduced the CD45+ T cells infiltration, and increased CD4+FoxP3+ regulatory T cells population and reduced kidney injury as evident by reduced plasma creatinine. However, BUN and proteinuria analysis did not suggest any significant changes with AT2R activation at 3 day post-IR. The ex-vivo splenic CD4+T cells revealed that C21 treatment modulated the CD4+T cells into CD4+Treg cells as determined by 2- fold increase in transcription factor FoxP3 expression. AT2R antagonist PD123319 reduced 2- fold, suggesting the involvement of AT2R. The PP2A inhibitor okadaic acid remarkably attenuated C21-induced FoxP3 increase indicating while the NO synthase inhibitor L-NAME caused only a moderate reduction in C21-induced FoxP3 expression.
IR causes a lower immune cell infiltration in females than males and the AT2R-mediated protection and Treg modulation occurs via PP2A pathway.
- Other NIH Support