title: Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys.
abstract: 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 long-term or short-term nephrin knockdown challenged with uninephrectomy or doxorubicin. Taken together, our data establish that under the basal condition and in acquired glomerular diseases, nephrin is required to maintain slit diaphragm integrity and slit diaphragm-mediated signaling to preserve glomerular function and podocyte viability in adult mice.
authors: Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Nephrology; Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
authors: Xuezhu
authors: X
authors: Li
authors: Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York; chuanp01@gmail.com.
authors: Peter Y
authors: PY
authors: Chuang
authors: Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York;
authors: Vivette D
authors: VD
authors: D'Agati
authors: Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Nephrology, Shanghai First Municipal Hospital, Shanghai Jiaotao University School of Medicine; Shanghai, China;
authors: Yan
authors: Y
authors: Dai
authors: Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York;
authors: Rabi
authors: R
authors: Yacoub
authors: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China;
authors: Jia
authors: J
authors: Fu
authors: Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York;
authors: Jin
authors: J
authors: Xu
authors: State University of New York at University at Binghamton, Binghamton, New York;
authors: Oltjon
authors: O
authors: Taku
authors: Mirimus, Inc. Cold Spring Harbor, New York;
authors: Prem K
authors: PK
authors: Premsrirut
authors: Renal Electrolyte and Hypertension Division, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; and.
authors: Lawrence B
authors: LB
authors: Holzman
authors: Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York; Renal Section, James J Peter Veterans Administration Medical Center, Bronx, New York.
authors: John Cijiang
authors: JC
authors: He
mesh_terms: D000367:Age Factors; D000818:Animals; D002470:Cell Survival; D007678:Kidney Glomerulus / Q000033:anatomy & histology* / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000166:cytology* / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C113267:nephrin
keywords: animal model; glomerulopathy; kidney disease; nephrin; podocyte; slit diaphragm
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