Sex Differences in renal ischemia-reperfusion injury following deletion of Netrin-1 in the kidney

Abstract

Netrin-1, an angiogenic guidance cue, is heavily expressed in the kidney. Our lab has previously reported that deletion of Netrin-1 in Foxd1-positive stromal progenitors ( Foxd1 GC/+ Netrin1 fl/fl ) results in abnormal vascular patterning during kidney development, including a reduction in interlobar branching. It remains unknown how these changes in vascular patterning affect kidney function and physiology. In the current study, we hypothesized that changes in developmental patterning of the kidney vasculature would protect from renal ischemia-reperfusion injury in a sex-specific manner due to ischemic preconditioning to the kidney tubular cells. To test this hypothesis, we performed warm, bilateral ischemia-reperfusion by clamping the renal pedicles for 26-minutes in wild-type ( Netrin1 fl/fl or Netrin1 fl/+ )(3M, 3F), heterozygous ( Foxd1 GC/+ Netrin1 fl/+ ) (2M, 4F), and mutant ( Foxd1 GC/+ Netrin1 fl/fl ) (3M, 1F) male (M) and female (F) mice. Following 24-hours of reperfusion, blood and kidneys were collected for analysis of kidney injury markers. We found that plasma creatinine (p 2-wayANOVA =0.021) and blood urea nitrogen (p 2-wayANOVA =0.009) were decreased in female mice compared to male mice regardless of genotype. In both male and female mutant mice, there was a decrease in these markers of injury compared to heterozygous and wild-type control mice, although this did not reach statistical significance. In agreement, immunofluorescent staining of kidney injury marker 1 (KIM-1) indicated less tubular injury in female mice compared to males. These data suggest that female mice are less susceptible to ischemic injury than male mice despite both sexes having similar alterations in vascular patterning following deletion of Netrin-1. Further, our results indicate a protective effect of these developmental patterning changes due to Netrin-1 deletion. We suspect that changes in the vasculature in our mutant mice provide a preconditioning-like environment to mediate this effect. Future studies will investigate the underlying mechanisms which drive this injury phenotype between sexes. Understanding how renal vascular development impacts kidney injury is critical to the development of new therapeutic strategies to prevent the sustained injury following periods of ischemia. NIH R01DK121014 to LO This is the full abstract presented at the American Physiology Summit 2023 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.