Altered renal vascular patterning reduces ischemic kidney injury and limits age-associated vascular loss

The kidney vasculature has a complex arrangement, which runs in both series and parallel to perfuse the renal tissue and appropriately filter plasma. Recent studies have demonstrated that the development of this vascular pattern is dependent on netrin-1 secreted by renal stromal progenitors. Mice lacking netrin-1 (<i>Ntn1</i>) from these cells develop an arterial tree with stochastic branching, particularly of the large interlobar vessels. The current study investigated whether abnormalities in renal vascular patterning altered kidney function or response to injury. To examine this, we analyzed kidney function at baseline as well as in response to a model of bilateral ischemic injury and measured vascular dynamics in 7- to 8-mo-old mice. We found no differences in kidney function or morphology at baseline between mice with an abnormal arterial pattern compared with control. Interestingly, male and female mutant mice with stochastic vascular patterning showed a reduction in tubular injury in response to ischemia. Similarly, mutant mice also had a preservation of perfused vasculature with increased age compared with a reduction in the control group. These results suggest that guided and organized patterning of the renal vasculature may not be required for normal kidney function, but uncovers new implications for patterning in response to injury. Understanding how patterning and maturation of the arterial tree affects physiology and response to injury has important implications for enhancing kidney regeneration and tissue engineering strategies.<b>NEW & NOTEWORTHY</b> Kidney vascular patterning is established through responses to guidance cues such as netrin-1; however, the significance of proper patterning to function and injury response remains unexplored. Here, utilizing a conditional knockout of netrin-1 (<i>Ntn1</i>) that displays persistent abnormal arterial patterning, we identify no significant disruptions to normal kidney physiology in adult animals but, surprisingly, less tubular damage in response to ischemic injury. This study uncovers new and significant implications for proper kidney vascular patterning.