Background: Glutathione-S-transferase Mu1( Gstm1 ) gene, a member of Glutathione-S-transferases (GST) superfamily, encodes an enzyme that functions in the detoxification of electrophilic compounds. The common GSTM1 deletion variant in humans is associated with increased risks of chronic kidney disease (CKD) progression and incident end stage kidney failure. We reported that deletion of Gstm1 increases oxidative stress, kidney inflammation and injury in angiotensin II induced hypertension (Ang II-HTN) in mice. At 4 weeks of Ang II-HTN, neutrophils, CD4+T cells, and F4/80+ cells were significantly increased in Gstm1 knockout (KO) kidney. While a link between oxidative stress and immune activation in hypertension has been well documented, the molecular mechanism by which Gstm1 regulates immune cell activation in hypertension is unknown. Methods: To further characterize the inflammatory response in GSTM1 deficiency, Gstm1 KO and wild-type (WT) male mice at ~ 12 weeks of age were subjected to Angiotensin II at 1000 ng/kg per minute for 4 days via a mini osmotic pump. The kidney cells and bone marrow cells were isolated for flow cytometry analysis. Results: At baseline, there were no differences in inflammatory cell populations including neutrophils between WT and Gstm1 KO mice. At Day 4 of Ang II-HTN, Gstm1 KO kidneys exhibited about a 2.3 fold increase in neutrophil population (CD45 + Ly6G + CD11b + ), compared to WT control mice (10 WT and 8 Gstm1 KO mice, p=0.0075). Interestingly, CD45+ bone marrow cells isolated from both Gstm1 KO and WT mice have similar percentile of neutrophil populations ; however, neutrophils in Gstm1 KO bone marrow express relatively higher levels of CXCR2. Unlike at 4 weeks, there was no difference in other inflammatory cells at Day 4. Conclusion: Deletion of Gstm1 increases renal neutrophil population early in Ang II-HTN and CXCR2 expression in bone marrow neutrophils. Gstm1 may play a role in regulating neutrophil migration and recruitment. Further studies are needed to delineate whether GSTM1 deficiency drives kidney injury via early neutrophil migration, which could shed light on potential therapeutic target for CKD progression in those genetically susceptible.

Nuclear Factor of Activated T Cells 1 (NFATC1) plays a role in the immune response and has been shown to be required for cardiac development. A recent trans-ethnic meta-analysis of genome-wide association studies (GWAS) found the NFATC1 gene in humans was associated with estimated glomerular filtration rate (eGFR). Further studies in salt-sensitive mice showed a decrease in renal Nfact1 mRNA expression during high-salt exposure, suggesting a link between NFATC1 and salt-sensitive hypertension. Here, we backcrossed a knockout mouse model of Nfatc1 to a salt-sensitive 129S6 background for 6 generations. Heterozygous (Het) and wild-type (WT) male mice at 8-12 weeks of age were trained for blood pressure measurement by tail cuff manometry over 2 weeks, and measurements were taken over the following week while on standard chow (NSD), and again for 2+1 weeks while on a matched high-salt diet (HSD, 6% total NaCl). On NSD, there was no difference in SBP between WT and Het mice. However, while WT mice displayed an expected elevation in SBP on HSD, Het mice showed no change in SBP, resulting in a statistically significant difference between genotypes (140.7±11.1 mmHg vs 125.7±9.7 mmHg, p = 0.02, n = 8/6). This preliminary data suggests that down-regulation of Nfatc1 under HSD may be a compensatory response to limit the rise in blood pressure during high salt consumption, and that NFATC1 may be a therapeutic target for salt-sensitive hypertension. Further studies are underway to delineate the molecular mechanism by which Nfatc1 mediates salt-sensitivity.