Gut Microbiome and Olfactory Receptor 78 in Experimental AKI

Background: Olfactory receptor 78 (Olfr78) is a short-chain fatty acid (SCFA) receptor activated by gut microbiome-derived acetate and propionate. Olfr78 is expressed in the afferent arteriole, vascular smooth muscle cells, and immune cells. SCFAs are hypothesized to mediate gut microbiome effects in AKI and CKD. We studied the role of Olfr78 in ischemic and cisplatin induced AKI in mice. Methods: Male and female, wild-type (WT) and Olfr78 knockout (KO) C57BL6 mice were subjected to bilateral ischemic or cisplatin AKI. Mice were also studied long-term after severe unilateral ischemic AKI (UIRI). Endpoints included survival, kidney function (SCr, GFR by FITC-sinistrin clearance), histology and kidney immune cell phenotyping (FACS). Results: In moderate bilateral ischemic AKI, Olfr78 KO mice had worse survival at 72 hrs than WT mice (P<0.01). However, no changes were found in kidney function or structure. Cisplatin induced AKI was comparable in KO and WT mice. Female mice were more susceptible to cisplatin, while males more susceptible to ischemic AKI. In the UIRI model, KO had lower GFR than WT at baseline (1369.9±106.4 vs 1170.7±196.5, P≤0.05), 24h after UIRI (959.4±8 vs 837.0±7, P< 0.05) and after 21d (1166.1±54.5vs 807.6±11, P< 0.0001). After severe UIRI KO mice showed a decrease in double negative (DN) (9.6±1.6 vs 4.0±1.6%, P<0.001) and increase in double-positive cells (DP) T cells (0.2±0.1 vs 0.5±0.3%, P<0.001). In the CD4 subset, activation marker CD69 (32.6±4.0 vs 74.8±7.6%, P< 0.0001), effector cells (CD44+CD62L-) (93.1±1.2 vs 94.6 ±0.93%, P<0.05), and immune checkpoint molecule TIGIT (12.8±4.5 vs 21.9±3.9%, P<0.01) increased in KO vs. WT. In CD8 cells, there was an increase in CD69 (40.8±8.8 vs 55.8±8.6%, P<0.01), TIGIT (7.9±2.4 vs 17.4±11.3 %, P<0.01) and CTLA4 (0.1±0.14 vs 0.7 ±0.5%, P<0.01); There was a decrease in B cells (25.5±2.4 vs 15.7±2.2, P<0.001) and an increase in NKT cells (1.0±0.3 vs 2.4±0.70, P<0.001) and dendritic cells (2.0±2.2 vs 5.4±6.3, P<0.001) in Olfr78 KO vs. WT. Conclusion: Absence of Olfr78 reduced short-term survival after moderate AKI, but with minimal effects on renal function/structure. However, GFR and kidney immunophenotypes were modified by Olfr78 after severe UIRI. Olfr78 has subtle effects during AKI but is likely not a major mechanism by which gut microbiome influences outcomes in AKI. Funding: NIDDK Support