Deletion of Piezo2 from renal Foxd1+ stromal progenitors and descendent cells results in abnormal mesangial development and sex-specific differences in kidney function

Abstract

Piezo2 is a mechanically activated ion channel recently identified in glomerular mesangial cells and renin+ juxtaglomerular (JG) cells. Despite several studies which confirm this localization of Piezo2 in the kidney, the function of Piezo2 in these cells remains ambiguous. In the current study, we hypothesized that loss of Piezo2 in mesangial and JG cells would result in abnormal glomerular development during nephrogenesis and impaired salt and water balance in adult mice. To test this hypothesis, we generated mutant mice lacking Piezo2 in Foxd1+ stromal progenitors and their cell lineages, which include mesangial and JG cells. Kidney morphology was assessed by immunofluorescent staining and z-stack confocal microscopy during late nephrogenesis (post-natal day 0, P0) and following maturation of the nephron (P20) in wild-type (Piezo2fl/fl, n=3), heterozygous (Foxd1GC/+Piezo2fl/+, n=3), and mutant (Foxd1GC/+Piezo2fl/fl, n=3) mice. In adult male and female mice (n=2/genotype/sex), blood pressure was measured by tail cuff (CODA Systems) between 1-4pm following 3 days of acclimation. In a separate group of control and mutant male and female mice (8-10 weeks, n=3-5/group/sex), a 4-hour saline challenge (i.p. 10% body weight) was performed to assess diuresis and natriuresis. At P0, we found that deletion of Piezo2 from Foxd1+ stromal progenitors and their cell lineages resulted in the abnormal distribution of mesangial cells within glomeruli, such that the mesangial area appears compressed compared to control or heterozygous mice. This phenotype was exacerbated in mutant mice by P20. In adult mice, female mutants had an increase in daytime mean arterial pressure (~10mmHg, mean 79 vs 88) compared to female controls. Cumulative urine excretion (4 hours, percent injected) was decreased in females compared to males, regardless of genotype (p<0.001). Further, female mutant mice had a delayed diuresis response compared to control (2 hour, mean 16% vs 28% cumulative urine volume). However by 4 hours following a saline bolus both groups were similar. Taken together, these data indicate that deletion of Piezo2 in Foxd1+ stromal progenitors results in impairments in mesangial cell development during nephrogenesis and alterations in water and salt balance in adult female mice. Understanding the sex-specific roles of Piezo2 in kidney development and physiology is critical to identify the role of mechanosensation on renal homeostasis. NIH R01DK121014 to LO. This is the full abstract presented at the American Physiology Summit 2024 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.