Pippin, J. W.; Armour, C. R.; Eng, D. G.; Tran, U.; Kavarina, N.; Dill-McFarland, K. A.; Wessely, O.; Shankland, S. J.

There are regional differences in the kidney in focal segmental glomerulosclerosis (FSGS) where podocyte injury is more severe in the juxta-medulla (JM) compared to the outer cortex (OC). Single nuclear RNA-sequencing was performed to determine any regional transcriptomic differences. 1055 differentially expressed genes (DEGs) were identified between healthy OC and JM podocytes. Of 53 podocyte canonical genes, only Magi1 and Mapt, and Npnt were higher in healthy OC and JM podocytes respectively. Hallmark pathway analysis showed that in normal mice, healthy JM podocytes are enriched for oxidative phosphorylation, glycolysis and fatty acid metabolism compared to OC podocytes. At day 7 in an experimental FSGS model induced in mice with a cytopathic anti-podocyte antibody, 226 and 225 DEGs were higher in OC and JM podocytes respectively, and 166 overlapped. Five podocyte subclusters were identified, of which the most severe (subcluster 4) was enriched for a senescence phenotype, including the p53 pathway. Inducing FSGS in mice in which p53 was deleted specifically in podocytes had lower glomerular injury compared to diseased wildtype mice. These results are consistent with differences in podocytes in the OC and JM, which might underlie regional differences in FSGS.