Aggarwal Pardeep K, Veron Delma, Thomas David B, Siegel Dionicio, Moeckel Gilbert, Kashgarian Michael, Tufro Alda
Department of Pediatrics/Nephrology, Yale University School of Medicine, New Haven, CT.
Department of Pathology, University of Miami Miller School of Medicine, Miami, FL.
Diabetes. 2015 May;64(5):1743-59. doi: 10.2337/db14-0719. Epub 2014 Dec 4.
The onset of diabetic nephropathy (DN) is highlighted by glomerular filtration barrier abnormalities. Identifying pathogenic factors and targetable pathways driving DN is crucial to developing novel therapies and improving the disease outcome. Semaphorin3a (sema3a) is a guidance protein secreted by podocytes. Excess sema3a disrupts the glomerular filtration barrier. Here, using immunohistochemistry, we show increased podocyte SEMA3A in renal biopsies from patients with advanced DN. Using inducible, podocyte-specific Sema3a gain-of-function (Sema3a(+)) mice made diabetic with streptozotocin, we demonstrate that sema3a is pathogenic in DN. Diabetic Sema3a(+) mice develop massive proteinuria, renal insufficiency, and extensive nodular glomerulosclerosis, mimicking advanced DN in humans. In diabetic mice, Sema3a(+) exacerbates laminin and collagen IV accumulation in Kimmelstiel-Wilson-like glomerular nodules and causes diffuse podocyte foot process effacement and F-actin collapse via nephrin, αvβ3 integrin, and MICAL1 interactions with plexinA1. MICAL1 knockdown and sema3a inhibition render podocytes not susceptible to sema3a-induced shape changes, indicating that MICAL1 mediates sema3a-induced podocyte F-actin collapse. Moreover, sema3a binding inhibition or podocyte-specific plexinA1 deletion markedly ameliorates albuminuria and abrogates renal insufficiency and the diabetic nodular glomerulosclerosis phenotype of diabetic Sema3a(+) mice. Collectively, these findings indicate that excess sema3a promotes severe diabetic nephropathy and identifies novel potential therapeutic targets for DN.
糖尿病肾病（DN）的发病以肾小球滤过屏障异常为突出表现。识别驱动DN的致病因素和可靶向的通路对于开发新疗法和改善疾病预后至关重要。信号素3a（sema3a）是足细胞分泌的一种导向蛋白。过量的sema3a会破坏肾小球滤过屏障。在此，我们通过免疫组织化学显示，晚期DN患者肾活检中足细胞SEMA3A增加。利用链脲佐菌素诱导制成糖尿病的、足细胞特异性sema3a功能获得性（Sema3a(+)）小鼠，我们证明sema3a在DN中具有致病性。糖尿病Sema3a(+)小鼠出现大量蛋白尿、肾功能不全和广泛的结节性肾小球硬化，类似于人类的晚期DN。在糖尿病小鼠中，Sema3a(+)会加剧Kimmelstiel-Wilson样肾小球结节中层粘连蛋白和IV型胶原的积累，并通过nephrin、αvβ3整合素以及MICAL1与丛状蛋白A1的相互作用导致弥漫性足细胞足突消失和F-肌动蛋白塌陷。敲低MICAL1和抑制sema3a可使足细胞不易受到sema3a诱导的形态变化影响，表明MICAL1介导sema3a诱导的足细胞F-肌动蛋白塌陷。此外，抑制sema3a结合或足细胞特异性缺失丛状蛋白A1可显著改善蛋白尿，并消除糖尿病Sema3a(+)小鼠的肾功能不全和糖尿病结节性肾小球硬化表型。总体而言，这些发现表明过量的sema3a会促进严重的糖尿病肾病，并确定了DN新的潜在治疗靶点。
