Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys

作者：Xuezhu Li, Peter Y. Chuang, Vivette D. D’Agati, Yan Dai, Rabi Yacoub, Jia Fu, Jin Xu, Oltjon Taku, Prem K. Premsrirut, Lawrence B. Holzman, John Cijiang He · 发表于：Journal of the American Society of Nephrology · 年份：2015 · DOI：10.1681/asn.2014040405 · 被引用次数：131 · 研究领域：Renal Diseases and Glomerulopathies、Renal and related cancers、Chronic Kidney Disease and Diabetes

Nephrin is required during kidney development for the maturation of podocytes and formation of the slit diaphragm junctional complex. Because nephrin expression is downregulated in acquired glomerular diseases, nephrin deficiency is considered a pathologic feature of glomerular injury. However, whether nephrin deficiency exacerbates glomerular injury in glomerular diseases has not been experimentally confirmed. Here, we generated mice with inducible RNA interference-mediated nephrin knockdown. Short-term nephrin knockdown (6 weeks), starting after the completion of kidney development at 5 weeks of age, did not affect glomerular structure or function. In contrast, mice with long-term nephrin knockdown (20 weeks) developed mild proteinuria, foot process effacement, filtration slit narrowing, mesangial hypercellularity and sclerosis, glomerular basement membrane thickening, subendothelial zone widening, and podocyte apoptosis. When subjected to an acquired glomerular insult induced by unilateral nephrectomy or doxorubicin, mice with short-term nephrin knockdown developed more severe glomerular injury compared with mice without nephrin knockdown. Additionally, nephrin-knockdown mice developed more exaggerated glomerular enlargement when subjected to unilateral nephrectomy and more podocyte apoptosis and depletion after doxorubicin challenge. AKT phosphorylation, which is a slit diaphragm-mediated and nephrin-dependent pathway in the podocyte, was markedly reduced in mice with lon...