CD148 agonistic antibody alleviates renal injury induced by chronic angiotensin II infusion in mice.

IF 2.2 4区 医学 Q2 UROLOGY & NEPHROLOGY
Keiko Takahashi, Alina Yu, Tadashi Otsuka, Lejla Pasic, Chikage Narui, Lilly He, Philipp Ellinger, Manuel Grundmann, Raymond C Harris, Takamune Takahashi
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Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: Agonistic CD148 antibody attenuates UNx + Ang II-induced renal injury, in part by reducing EGFR activity.

CD148激动抗体减轻慢性血管紧张素II输注所致小鼠肾损伤。
背景:血管紧张素II (Ang II)在肾脏疾病的进展中起关键作用。除了其直接信号事件外,Ang II还可激活表皮生长因子受体(EGFR)并引起肾损伤。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。在这项研究中,我们研究了CD148激动抗体18E1 mAb是否能减轻慢性Ang II输注引起的肾损伤,以探索其治疗应用。方法:单侧肾切除术(UNx)小鼠经渗透小泵输注Ang II (1.4 mg/kg / d),连续6周诱导高血压肾病。将18E1 mAb或同型对照IgG (15 mg/kg,每周3次)腹腔注射至UNx + Ang II小鼠,持续6周,观察其肾脏表型。结果:长期输注angii可引起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、肾肥大、足细胞损伤、巨噬细胞浸润、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显著降低了这些肾脏变化,而对血压没有影响。此外,phospho-EGFR免疫组织化学和免疫印迹显示,在接受UNx和Ang II输注的小鼠肾脏中,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。结论:激动性CD148抗体减轻UNx + Ang ii诱导的肾损伤,部分原因是通过降低EGFR活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMC Nephrology
BMC Nephrology UROLOGY & NEPHROLOGY-
CiteScore
4.30
自引率
0.00%
发文量
375
审稿时长
3-8 weeks
期刊介绍: BMC Nephrology is an open access journal publishing original peer-reviewed research articles in all aspects of the prevention, diagnosis and management of kidney and associated disorders, as well as related molecular genetics, pathophysiology, and epidemiology.
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