Takahashi Keiko, Yu Alina, Otsuka Tadashi, Pasic Lejla, Narui Chikage, He Lilly, Ellinger Philipp, Grundmann Manuel, Harris Raymond C, Takahashi Takamune
Division of Nephrology and Hypertension, Vanderbilt University Medical Center, S-3223 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232, USA.
Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
BMC Nephrol. 2025 Mar 31;26(1):165. doi: 10.1186/s12882-025-04070-x.
Angiotensin II (Ang II) plays a critical role in the progression of kidney disease. In addition to its direct signaling events, Ang II transactivates epidermal growth factor receptor (EGFR) and causes renal injury. CD148 is a transmembrane protein tyrosine phosphatase that dephosphorylates EGFR and strongly inhibits its activity. In this study, we have asked if CD148 agonistic antibody 18E1 mAb attenuates renal injury induced by chronic Ang II infusion to explore its therapeutic application.
Hypertensive nephropathy was induced in mice subjected to unilateral nephrectomy (UNx) by infusing Ang II (1.4 mg/kg per day) for 6 weeks using an osmotic minipump. The 18E1 mAb or isotype control IgG were intraperitoneally injected (15 mg/kg, three times per week) to the UNx + Ang II mice for 6 weeks, and their renal phenotype was investigated.
Chronic Ang II infusion induced evident hypertension and renal injury that is indicated by elevation of plasma creatinine, urinary albumin excretion, renal hypertrophy, podocyte injury, macrophage infiltration, and the expression of alpha smooth muscle actin and collagen deposition. As compared with isotype control antibody, 18E1 mAb significantly reduced these renal changes, while it showed no effects on blood pressure. Furthermore, phospho-EGFR immunohistochemistry and immunoblotting demonstrated renal EGFR is activated in the mice that were subjected to UNx and Ang II infusion and 18E1 mAb significantly reduces EGFR phosphorylation in these kidneys as compared with isotype control treatment.
Agonistic CD148 antibody attenuates UNx + Ang II-induced renal injury, in part by reducing EGFR activity.
血管紧张素II（Ang II）在肾脏疾病进展中起关键作用。除其直接信号转导事件外，Ang II还可反式激活表皮生长因子受体（EGFR）并导致肾损伤。CD148是一种跨膜蛋白酪氨酸磷酸酶，可使EGFR去磷酸化并强烈抑制其活性。在本研究中，我们探究了CD148激动性抗体18E1单克隆抗体（mAb）是否能减轻慢性输注Ang II诱导的肾损伤，以探索其治疗应用。
通过使用渗透微型泵每天输注Ang II（1.4 mg/kg）持续6周，在单侧肾切除（UNx）的小鼠中诱导高血压肾病。将18E1 mAb或同型对照IgG腹腔注射（15 mg/kg，每周三次）给UNx + Ang II小鼠，持续6周，并研究其肾脏表型。
慢性输注Ang II诱导明显的高血压和肾损伤，表现为血浆肌酐升高、尿白蛋白排泄增加、肾脏肥大、足细胞损伤、巨噬细胞浸润以及α平滑肌肌动蛋白表达和胶原沉积。与同型对照抗体相比，18E1 mAb显著减轻了这些肾脏变化，而对血压无影响。此外，磷酸化EGFR免疫组织化学和免疫印迹显示，在接受UNx和输注Ang II的小鼠中，肾脏EGFR被激活，与同型对照治疗相比，18E1 mAb显著降低了这些肾脏中EGFR的磷酸化。
激动性CD148抗体可减轻UNx + Ang II诱导的肾损伤，部分原因是通过降低EGFR活性。
