Netrin-1 is an angiogenic guidance cue expressed in the developing kidney. Our lab, and others, have previously reported that deletion of netrin-1 (Ntn1) from kidney interstitial progenitors results in abnormal vascular patterning and delayed vascular smooth muscle coverage. Despite these changes to the renal vasculature, we found that Ntn1 mutant mice had reduced tubular injury following kidney ischemia compared with controls in both male and female mice. However, the mechanisms which contribute to this decrease in ischemic tubular injury remain unknown. In the current study, we investigated whether renal vascular mispatterning in Ntn1 mutants alters regional blood flow in the kidney. To test this, we utilized laser doppler flow probes (Transonic Systems Inc.) in anesthetized control (Ntn1fl/fl, n=3) and mutant (Foxd1GC/+Ntn1fl/fl, n=4) female mice (4 months old). The left kidney was exposed via dorsal flank incision and flow probes were inserted into the cortex (approx. 1mm depth) and medulla (approx. 3mm depth). Following a 10-minute stabilization period, baseline flow was recorded (PowerLab 4/35 and LabChart 8) for 15-minutes. An atraumatic vascular clamp (Fine Science Tools) was then placed on the left renal artery and vein for 26-minutes. Following removal of the clamp, reperfusion blood flow was recorded for 20-minutes. We found that baseline (pre-ischemia) blood flow was similar between control and Ntn1 mutant mice in both the cortex (p2-wayRM=0.36) and medulla (p2-wayRM=0.85). Further, we saw no differences in blood flow between genotypes during reperfusion in the cortex (p2-wayRM=0.50) or medulla (p2-wayRM=0.58) after 26-minutes of ischemia. These data suggest that despite abnormal renal vascular patterning in Ntn1 mutant mice, regional blood flow is similar to controls. In addition, these data indicate that changes to the timing or rate of reperfusion are not responsible for the decrease in tubular injury following ischemia in female mice. These results are important as they suggest that the mechanism(s) that contribute to attenuated kidney injury in Ntn1 mutant mice are likely due to molecular adaptations rather than alterations in vascular tone. Therefore, future studies will utilize RNA sequencing to determine specific targets in tubular or vascular cells which facilitate this response. Identifying the molecular mediators of this interplay and enhanced injury response have important implications for identifying novel vascular targeting strategies to improve kidney repair. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
McLarnon et al. (Fri,) studied this question.