Deletion of PREX1 (Phosphatidylinositol-3,4,5-trisphosphate Dependent Rac Exchange Factor 1) Worsens Salt Sensitive Hypertension and Kidney Damage in Dahl S Rats

Prex1 (Phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1) is a Rac-specific guanine nucleotide exchanging factor and an integrator of signaling between Rac1 and protein kinase A (PKA). Both Rac1 and PKA are involved in pathways associated with salt sensitive hypertension. However, the roe of Prex1 in renal function and salt sensitive hypertension has not been studied. To investigate the role of Prex1 in salt sensitive hypertension. We used a Prex1 knockout (KO) rat on the Dahl salt sensitive genetic background generated by the RGERC at the Medical College of Wisconsin. Genotyping showed that the Prex1 gene was deleted. We studied the expression and localization of Prex1 in kidney sections using immunolabeling and confocal microscopy. Prex1 protein was mainly located in renal tubules, infiltrating inflammatory cells, and endothelial cells of large vessels. We then studied if deletion of Prex1 altered salt sensitivity of blood pressure. We found that both male and female WT Dahl S and Prex1 KO developed salt sensitivity after 2 weeks of 4% high salt diet. However, the increase in blood pressure was higher in male Prex1 KO Dahl S rats (Prex1 KO: 33± 7, vs male WT: 19± 2 mmHg, p<0.05). In females Prex1 KO, high salt increased BP by 31± 3 mmHg whereas the increase was lower in female WT Dahl S (17± 1 mmHg, p<0.05). Rats were placed in metabolic cages for urine collection. Male rats had increased albuminuria after high salt diet for 2 weeks that was not different between WT and Prex1 KO. Female rats had a smaller increase in albuminuria which was not different between WT and KO. Given the expression of Prex1 in inflammatory cells we quantified macrophage infiltration in the kidney after high salt diet. Male Prex1 KO rats had significantly higher macrophage infiltration compared to WT (WT: 141±10 vs Prex1 KO: 337± 18, p<0.05). Female Prex1 KO rats also had higher macrophage infiltration after high salt diet, but the total number of macrophages was lower than males (103 ± 7 female WT vs 208 ± 18 female Prex1 KO). We conclude that Prex1 protects against salt sensitive hypertension and inflammatory cell infiltration in Dahl salt sensitive rats such that its deletion worsens both phenotypes. Females Dahl S were somewhat protected against salt induced hypertension and this response was not worsened in Prex1 KO. Future experiments will study the role of Prex1 in renal NaCl transport. NIDDK-R56DK131114 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.