Neuropilin 1 Expressed in Resident Fibroblasts Protects Kidneys from Development of Fibrosis

Background: Renal fibrosis is the common end point of Chronic Kidney Disease (CKD), the hallmark of which is the deposition of pathological extracellular matrix by myofibroblasts. Experiments with lineage tracing in mice and single-cell RNAseq in humans revealed that resident fibroblasts/pericytes are the major sources of myofibroblasts during CKD progression. Neuropilin 1 (NRP1) is a membrane-bound coreceptor for class 3 semaphorins and for specific isoforms of vascular endothelial growth factor. Importantly, NRP1 plays a critical role in fibrosis progression in various pathophysiological conditions such as liver cirrhosis and tumor proliferation and metastasis. In the kidney, NRP1 is expressed in resident fibroblasts/pericytes of the renal interstitium. We therefore tested the possibility that NRP1 could participate in a cell-autonomous manner in the development of renal fibrosis Methods: We used the myelin protein zero-Cre (P0-Cre) strain of mice to invalidate the expression of Nrp1 constitutively in resident fibroblasts of the kidney. Nrp1-ko mutants (P0-Cre, Nrp1flox/flox, RosaYFP) and wildtype littermates were subjected to two well-characterized models of renal fibrosis: the folic acid (FA) nephrotoxicity model and the unilateral ureteral obstruction (UUO) model. In separate experiments, we used angiotensin II (Ang II) administration through an osmotic minipump to generate cardiac fibrosis. Results: We found that Nrp1-ko displayed proliferative defects that affected renal recovery after acute kidney injury. Accordingly, the renal function and structure of Nrp1-ko were significantly more impaired than those of their wildtype littermates in FA-induced renal disease. Similar observations were done in Nrp1-ko subjected to UUO. Our lineage tracing experiments showed that renal and cardiac interstitial cells derived from the same P0-Cre positive progenitors. This observation led us to investigate the role of NRP1 in the progression of cardiac fibrosis. We found that after continuous Ang II infusion, the fibrotic lesions are more pronounced in the hearts of Nrp1-ko mice compared to those of their wildtype littermates. Conclusion: Our data suggest that NRP1 expressed in resident fibroblasts is a protective mechanism against the progression of fibrosis, and this mechanism appears to be common in the kidney and heart. Funding: Government Support – Non-U.S.