Interrogating the Role of Vascular Smooth Muscle Cells in Guiding Kidney Innervation and Development

Background: End-stage renal disease has only two treatment options: dialysis or transplant, highlighting a critical need for alternative therapies. Effective alternative therapeutic strategies such as ex vivo tissue engineering will rely on sufficient vascularization and innervation of the organ. This necessitates a thorough understanding of the developing vasculature and how it interacts with both the nerves and the kidney during development. Despite the importance of innervation and vascularization for proper kidney development, there is still little known about how signaling between the nerves and the vasculature influences kidney organogenesis. Methods: To interrogate this, we use iDISCO+ tissue clearing with light-sheet microscopy to elucidate the mechanisms of neurovascular development in the kidney. During the onset of kidney innervation in mice, nerves are tightly associated with vascular smooth muscle cells (VSMCs) in wild-type mice as well as in a model of aberrant vascular patterning. This association is tightly maintained throughout development. Using a mouse model of denervation, we found that loss of nerves decreases kidney glomerular number and increases tubule diameter, indicative of impaired nephron development. Taken together, we hypothesize that VSMCs play a critical role in guiding nerves to their appropriate location which is required for sufficient nephrogenesis. We have used a SMC-specific Cre mouse model paired with a diphtheria toxin (DTA) allele to assess the impact of ablating VSMCs on kidney development. Results: Our preliminary results suggest that VSMC ablation after the establishment of innervation alters nerve patterning in the kidney, and ablation before the start of innervation may impair early innervation. Conclusion: This suggests a key role for VSMCs in guiding proper innervation of the kidney throughout development. Future studies will continue using this VSMC ablation model to assess the role of these cells at different stages of organogenesis, uncovering their contribution to normal kidney development and innervation. Funding: NIDDK Support