Abstract 021: Activated Cd8 + T Cells Interact With Distal Convoluted Tubules To Promote Salt-sensitive Hypertension Through The Ifnγ-pdl1 Pathway

Background & Hypothesis: The immune system plays a critical role in the development of hypertension. We recently found that CD8 + T cells (CD8Ts) infiltrate the kidneys and stimulate distal convoluted tubular cells (DCTs), upregulating sodium-chloride co-transporter (NCC) activity, leading to excessive sodium retention. However, the precise molecules driving this direct interaction between CD8Ts and DCTs have not yet been identified. Here we hypothesize that activated CD8Ts release gamma interferon (IFNγ) that primes the tubular cell to express PDL1 which functions as a co-stimulatory ligand promoting interactions between activated CD8Ts and DCTs contributing to the development of salt-sensitive hypertension. We predict blocking this molecular pathway will reduce CD8T-homing into the kidney, lowering blood pressure. Results: We found that CD8Ts isolated from DOCA-salt treated hypertensive mice exhibit higher activity compared to those from sham normotensive mice. Pre-activated CD8Ts demonstrated augmented ability to interact with DCTs compared to naïve CD8Ts, and as a consequence, DCTs that had been co-cultured with pre-activated CD8Ts demonstrated increased expression of NCC (7 fold) and increased PDL1 and high sodium retention (47% vs. 0-3%). These effects were abolished by neutralizing IFNγ or knockdown of PDL1 in DCTs. In-vivo results verified the in-vitro studies. We found that IFNγ-KO mice demonstrated reduced blood pressure elevation and T cell infiltration within their kidneys to DOCA-salt compared to WT mice receiving the same treatment (last day systolic blood pressure average 155.2 mmHg compared to 189 mmHg from WT). Blood pressure elevation was blunted in DOCA-salt treated mice with renal tubule-specific knockdown of PDL1 (last day systolic blood pressure average 124 mmHg for mice with siPDL1 nanoparticle and 144 mmHg for mice with scrambled siRNA); NCC elevation was also blunted in this model. Conclusion: Activated CD8Ts demonstrate enhanced ability to interact with DCTs leading to increased expression of NCC and sodium retention through a IFNγ-PDL1 mediated mechanism. Blocking the IFNγ-PDL1 pathway prevents CD8T-DCT interaction both in vitro and in vivo , thereby ameliorating salt-sensitive hypertension.