Mice with a Pax2 missense variant display impaired glomerular repair.

Abstract

PAX2 regulates kidney development and its expression persists in parietal epithelial cells (PECs), potentially serving as a podocyte reserve. We hypothesize that mice with a Pax2 pathogenic missense variant (Pax2A220G/+) have impaired PEC-mediated podocyte regeneration. Embryonic wild type mouse kidneys showed overlapping expression of PAX2/WT-1 until PEC and podocyte differentiation, reflecting a close lineage relationship. Embryonic and adult Pax2A220G/+ mice have reduced nephron number but demonstrated no glomerular disease under baseline conditions. Pax2A220G/+ compared to wild type mice were more susceptible to glomerular disease after Adriamycin-induced podocyte injury, as demonstrated by worsened glomerular scarring, increased podocyte foot process effacement and podocyte loss. There was a decrease in PAX2-expressing PECs in wild type mice after Adriamycin injury accompanied by the occurrence of PAX2/WT-1 co-expressing glomerular tuft cells. In contrast, Pax2A220G/+ mice showed no changes in the numbers of PAX2-expressing PECs after Adriamycin injury, associated with fewer PAX2/WT-1 co-expressing glomerular tuft cells compared to injured wild type mice. A subset of PAX2 expressing glomerular tuft cells after Adriamycin injury was increased in Pax2A220G/+ mice, suggesting a pathologic process given the worse outcomes observed in this group. Lastly, Pax2A220G/+ mice have increased numbers of glomerular tuft cells expressing Ki67 and CC3 compared to wild type after Adriamycin injury, consistent with maladaptive responses to podocyte loss. Collectively, our results suggest that decreased glomerular numbers in Pax2A220G/+ mice are likely compounded with the inability of their mutated PECs to regenerate podocyte loss, and together these two mechanisms drive the worsened FSGS phenotype in these mice.