489-P: Loss of Neuropilin 1 in Podocytes Aggravates Diabetic Nephropathy

Podocyte injury is a crucial pathological event in diabetic nephropathy. Neuropilin 1 (NRP1) is a multi-functional transmembrane protein and functions as a co-receptor of extracellular ligands, such as VEGF. Previous studies have shown that NRP1 levels are significantly decreased in the kidney of diabetic patients, and advanced glycation end products down-regulate NRP1 in a mouse podocyte cell line. The function of NRP1 in podocytes has not been clearly understood. We found that NRP1 levels are significantly decreased in the glomeruli of db/db mice, STZ-induced diabetic mice and OVE26 mice. A podocyte-specific NRP1 knockout mouse strain (NRP1-CKO) is generated by crossbreeding NRP1^flox/flox mice with Nphs2-Cre transgenic mice. Compared to NRP1^flox/flox mice, the NRP1-CKO mice in the absence of diabetes showed increased 24h urine albumin excretion in the age of 2 months and a reduced creatinine clearance at the age of 4 months. Enlarged foot processes of podocytes and flattened podocyte body was found in NRP1-CKO mice, compared to age-matched NRP1^flox/flox mice. NRP1-CKO mice showed significantly decreased podocyte numbers per glomerulus and increased apoptosis. We generated diabetic NRP1-CKO mice (NRP1-CKO-OVE26) by crossbreeding the NRP1-CKO mice with OVE26 diabetic mice. NRP1-CKO/OVE26 diabetic mice developed more severe proteinuria, compared to the age- and genetic background-matched NRP1^flox/flox/OVE26 mice. As shown by PAS staining, the glomerular structure was disturbed, and glomerular mesangial expansion was more severe in NRP1-CKO/OVE26 mice. Phosphorylation of MAPKP38 was significantly elevated in the NRP1-deficient glomeruli, compared to age-matched NRP1^flox/flox glomeruli, suggesting that NRP1 deficiency induces activation of P38 signaling, further confirming podocyte stress and injury in NRP1-CKO mice. These results suggest that NRP1 ablation impairs renal function and exacerbates diabetic nephropathy and NRP1 is essential in the regulation of podocyte function and survival.