PMID- 25765888 OWN - NLM STAT- MEDLINE DCOM- 20160304 LR - 20181113 IS - 1873-4596 (Electronic) IS - 0891-5849 (Print) IS - 0891-5849 (Linking) VI - 84 DP - 2015 Jul TI - Lipopolysaccharide induces inducible nitric oxide synthase-dependent podocyte dysfunction via a hypoxia-inducible factor 1alpha and cell division control protein 42 and Ras-related C3 botulinum toxin substrate 1 pathway. PG - 185-195 LID - S0891-5849(15)00097-0 [pii] LID - 10.1016/j.freeradbiomed.2015.02.031 [doi] AB - Urine protein loss in immune complex-mediated diseases such as lupus nephritis is associated with podocyte foot process effacement (podocytopathy) but is not always dependent on glomerular immune complex deposition. Several murine and human studies have associated lupus nephritis with inducible nitric oxide synthase (iNOS) expression in what appear to be podocytes. This study was conducted to determine mechanisms of immune-complex-independent and iNOS-dependent podocyte dysfunction. Conditionally immortalized podocytes were cultured with lipopolysaccharide (LPS) and nitric oxide (NO), superoxide (SO), or peroxynitrite donors in the presence or absence of inhibitors of iNOS, reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase or monocyte chemotactic protein 1 (MCP-1), or with sepiapterin to increase coupling of iNOS homodimers. Podocyte NO, SO, and MCP-1 production and nitrotyrosine modifications were determined. The podocytopathy phenotype was determined by measuring cell motility and membrane permeability to albumin. This study determined that NO produced by iNOS is sufficient and necessary to induce podocytopathy. NO probably induces this phenotype via hypoxia-inducible factor 1alpha and cell division control protein 42 and Ras-related C3 botulinum toxin substrate 1 pathways. With LPS stimulation, neither SO nor peroxynitrite produced by uncoupled iNOS or NADPH oxidase nor MCP-1 was sufficient to induce the full phenotype. This study supports the notion that iNOS may induce autocrine podocyte dysfunction. Thus, targeting iNOS or the pathways of its induction may have therapeutic benefit. CI - Published by Elsevier Inc. FAU - Mashmoushi, Ahmad K AU - Mashmoushi AK AD - Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA. FAU - Oates, Jim C AU - Oates JC AD - Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA; Rheumatology Section, Medical Service, Ralph H. Johnson VA Medical Center, Charleston, SC 29401, USA. Electronic address: oatesjc@musc.edu. LA - eng GR - I01 CX000218/CX/CSRD VA/United States GR - R01 AR045476/AR/NIAMS NIH HHS/United States GR - R01AR045476/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20150309 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Ccl2 protein, mouse) RN - 0 (Cdc42 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Hif1a protein, mouse) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Lipopolysaccharides) RN - 0 (Neuropeptides) RN - 0 (Rac1 protein, mouse) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.13.39 (Nos2 protein, mouse) RN - EC 3.6.5.2 (cdc42 GTP-Binding Protein) RN - EC 3.6.5.2 (rac1 GTP-Binding Protein) SB - IM MH - Animals MH - Autocrine Communication MH - Cell Line MH - Cell Membrane Permeability MH - Cell Movement MH - Chemokine CCL2/biosynthesis MH - Enzyme Induction/drug effects MH - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism MH - Lipopolysaccharides/pharmacology MH - Mice, Transgenic MH - Neuropeptides/*metabolism MH - Nitric Oxide/biosynthesis MH - Nitric Oxide Synthase Type II/*genetics/metabolism MH - Podocytes/*enzymology/immunology MH - Protein Multimerization MH - Signal Transduction MH - cdc42 GTP-Binding Protein/*metabolism MH - rac1 GTP-Binding Protein/*metabolism PMC - PMC4457627 MID - NIHMS670692 OTO - NOTNLM OT - Cell division control protein 42 OT - Free radicals OT - Hypoxia-inducible factor 1alpha OT - Inducible nitric oxide synthase OT - Lipopolysaccharide OT - Lupus nephritis OT - Nitric oxide OT - Peroxynitrite OT - Podocyte OT - Ras-related C3 botulinum toxin substrate 1 OT - Superoxide OT - Toll-like receptor 4 EDAT- 2015/03/15 06:00 MHDA- 2016/03/05 06:00 PMCR- 2016/07/01 CRDT- 2015/03/14 06:00 PHST- 2014/09/19 00:00 [received] PHST- 2015/02/26 00:00 [revised] PHST- 2015/02/26 00:00 [accepted] PHST- 2015/03/14 06:00 [entrez] PHST- 2015/03/15 06:00 [pubmed] PHST- 2016/03/05 06:00 [medline] PHST- 2016/07/01 00:00 [pmc-release] AID - S0891-5849(15)00097-0 [pii] AID - 10.1016/j.freeradbiomed.2015.02.031 [doi] PST - ppublish SO - Free Radic Biol Med. 2015 Jul;84:185-195. doi: 10.1016/j.freeradbiomed.2015.02.031. Epub 2015 Mar 9.