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Agonistic anti-CD148 monoclonal antibody attenuates diabetic nephropathy in mice
Keiko Takahashi1, Rachel H Kim1, Lejla Pasic2
1Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee.
Abstract:
CD148 is a transmembrane protein tyrosine phosphatase (PTP) that is expressed in the renal vasculature, including the glomerulus. Previous studies have shown that CD148 plays a role in the negative regulation of growth factor signals (including epidermal growth factor and vascular endothelial growth factor), suppressing cell proliferation and transformation. However, the role of CD148 in kidney disease remains unknown. Here, we 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 (CD148KO) mice. The mAbs that increased 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 ip) in streptozotocin-induced wild-type and CD148KO diabetic mice for 6 wk, and the renal phenotype was then assessed. The effects of 18E1 mAb in podocyte growth factor signals were also assessed in culture. Compared with control IgG, 18E1 mAb significantly decreased albuminuria and mesangial expansion without altering hyperglycemia and blood pressure in wild-type diabetic mice. Immunohistochemical evaluation showed that 18E1 mAb significantly prevented the reduction of podocyte number and nephrin expression and decreased glomerular fibronectin expression and renal macrophage infiltration. The 18E1 mAb showed no effects in CD148KO diabetic mice. Furthermore, we demonstrated that 18E1 mAb reduces podocyte epidermal growth factor receptor signals in culture and in diabetic mice. These findings suggest that agonistic anti-CD148 mAb attenuates DN in mice, in part by reducing epidermal growth factor receptor signals in podocytes. This antibody may be used for the treatment of early DN.
Insights
An agonistic anti-CD148 antibody reduced kidney damage in diabetic mice by decreasing growth factor signals in podocytes. This antibody shows potential for treating early diabetic nephropathy.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- CD148 is a protein tyrosine phosphatase in the kidney vasculature that negatively regulates growth factor signaling.
- Its role in kidney disease, particularly diabetic nephropathy (DN), is currently unknown.
- Understanding CD148's function is crucial for developing new therapeutic strategies for DN.
Purpose of the Study:
- To investigate the therapeutic potential of an agonistic anti-CD148 antibody in a mouse model of diabetic nephropathy.
- To elucidate the mechanisms by which anti-CD148 antibody affects renal pathology and podocyte function.
- To assess the efficacy of targeting CD148 for the treatment of early-stage DN.
Main Methods:
- Generated agonistic anti-mouse CD148 monoclonal antibodies (mAbs) using CD148 knockout mice.
- Selected the most potent mAb (18E1) based on biological and biochemical assays.
- Administered 18E1 mAb to wild-type and CD148KO diabetic mice and assessed renal phenotype, including albuminuria, mesangial expansion, podocyte number, and inflammatory markers.
- Evaluated the effects of 18E1 mAb on podocyte growth factor signaling in vitro and in vivo.
Main Results:
- 18E1 mAb significantly reduced albuminuria and mesangial expansion in wild-type diabetic mice without affecting blood glucose or pressure.
- The antibody preserved podocyte number and nephrin expression, decreased fibronectin deposition, and reduced macrophage infiltration in glomeruli.
- No beneficial effects were observed in CD148 knockout diabetic mice, confirming the antibody's specificity.
- 18E1 mAb was shown to reduce epidermal growth factor receptor (EGFR) signaling in podocytes.
Conclusions:
- Agonistic anti-CD148 antibody (18E1 mAb) effectively attenuates diabetic nephropathy in mice.
- The therapeutic effect is mediated, in part, by the reduction of EGFR signaling in podocytes.
- This antibody represents a promising therapeutic candidate for early diabetic nephropathy treatment.
