Gagliardini Elena, Novelli Rubina, Corna Daniela, Zoja Carlamaria, Ruggiero Barbara, Benigni Ariela, Remuzzi Giuseppe
IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy;
IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; and Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
J Am Soc Nephrol. 2016 Apr;27(4):999-1005. doi: 10.1681/ASN.2015030266. Epub 2015 Aug 28.
The incidence of progressive kidney disease associated with diabetes continues to rise worldwide. Current standard therapy with angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers achieves only partial renoprotection, increasing the need for novel therapeutic approaches. Previous studies described B7-1 induction in podocytes of patients with proteinuria, including those with FSGS and type 2 diabetic nephropathy (DN). These findings sparked great excitement in the renal community, implying that abatacept, a costimulatory inhibitor that targets B7-1, could be a novel therapy for diabetic renal disease. Given previous concerns over the value of B7-1 immunostaining and the efficacy of abatacept in patients with recurrent FSGS after renal transplantation, we investigated B7-1 expression in human and experimental DN before embarking on clinical studies of the use of B7-1 targeting strategies to treat proteinuria in DN. Immunohistochemical analysis of kidney specimens using different antibodies revealed that B7-1 is not induced in podocytes of patients with DN, independent of disease stage, or BTBR ob/obmice, a model of type 2 diabetes. These results do not support the use of abatacept as a therapeutic strategy for targeting podocyte B7-1 for the prevention or treatment of DN.
在全球范围内，与糖尿病相关的进行性肾病的发病率持续上升。目前使用血管紧张素转换酶抑制剂和/或血管紧张素受体阻滞剂的标准治疗仅能实现部分肾脏保护，因此对新型治疗方法的需求日益增加。先前的研究描述了蛋白尿患者（包括局灶节段性肾小球硬化症和2型糖尿病肾病患者）足细胞中B7-1的诱导情况。这些发现引起了肾脏学界的极大关注，意味着靶向B7-1的共刺激抑制剂阿巴西普可能是治疗糖尿病肾病的一种新型疗法。鉴于先前对B7-1免疫染色的价值以及阿巴西普在肾移植后复发性局灶节段性肾小球硬化症患者中的疗效存在担忧，我们在开展使用靶向B7-1策略治疗糖尿病肾病蛋白尿的临床研究之前，研究了人类和实验性糖尿病肾病中B7-1的表达情况。使用不同抗体对肾脏标本进行免疫组织化学分析表明，在糖尿病肾病患者的足细胞中未诱导出B7-1，这与疾病阶段无关，在2型糖尿病模型BTBR ob/ob小鼠中也未诱导出B7-1。这些结果不支持将阿巴西普作为靶向足细胞B7-1预防或治疗糖尿病肾病的治疗策略。
