Agonistic anti-CD148 monoclonal antibody attenuates diabetic nephropathy in mice.
CD148 is a transmembrane protein tyrosine phosphatase (PTP) that is expressed in renal vasculature including the glomerulus. Previous studies have shown that CD148 plays a role in negative regulation of growth factor signals (including EGF and VEGF), suppressing cell proliferation and transformation. However, the role of CD148 in kidney disease remains unknown. Here, we have generated an agonistic anti-CD148 antibody and evaluated its effects in murine diabetic nephropathy (DN). Monoclonal antibodies (mAbs) against the mouse CD148 ectodomain sequence were generated by immunizing CD148 knockout (KO) mice. The mAbs that increase CD148 activity were selected by biological (proliferation) and biochemical (PTP activity) assays. The mAb (18E1) that showed strong agonistic activity was injected (10 mg/kg, i.p.) into streptozotocin-induced wild-type (WT) and CD148KO diabetic mice for 6 weeks, then renal phenotype was assessed. The effects of 18E1 mAb in podocyte growth factor signals were also assessed in culture. Compared to control IgG, 18E1 mAb significantly decreased albuminuria and mesangial expansion without altering hyperglycemia and blood pressure in WT diabetic mice. Immunohistochemical evaluation showed that 18E1 mAb significantly prevents the reduction of podocyte number and nephrin expression and decreases glomerular fibronectin expression and renal macrophage infiltration. The 18E1 mAb showed no effects in CD148KO diabetic mice. Furthermore, we demonstrate that 18E1 mAb reduces podocyte EGFR signals in culture and in diabetic mice. These findings suggest that agonistic anti-CD148 mAb attenuates DN in mice, in part by reducing EGFR signals in podocytes. This antibody may be used for the treatment of early DN.