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• W2894198112 abstract "Mutations in mitochondrial DNA as well as nuclear-encoded mitochondrial proteins have been reported to cause tubulointerstitial kidney diseases and focal segmental glomerulosclerosis (FSGS). Recently, genes and pathways affecting mitochondrial turnover and permeability have been implicated in adult-onset FSGS. Furthermore, dysfunctioning mitochondria may be capable of engaging intracellular innate immune-sensing pathways. To determine the impact of mitochondrial dysfunction in FSGS and secondary innate immune responses, we generated Cre/loxP transgenic mice to generate a loss-of-function deletion mutation of the complex IV assembly cofactor heme A:farnesyltransferase (COX10) restricted to cells of the developing nephrons. These mice develop severe, early-onset FSGS with innate immune activation and die prematurely with kidney failure. Mutant kidneys showed loss of glomerular and tubular epithelial function, epithelial apoptosis, and, in addition, a marked interferon response. In vitro modeling of Cox10 deletion in primary kidney epithelium compromises oxygen consumption, ATP generation, and induces oxidative stress. In addition, loss of Cox10 triggers a selective interferon response, which may be caused by the leak of mitochondrial DNA into the cytosol activating the intracellular DNA sensor, stimulator of interferon genes. This new animal model provides a mechanism to study mitochondrial dysfunction in vivo and demonstrates a direct link between mitochondrial dysfunction and intracellular innate immune response. Mutations in mitochondrial DNA as well as nuclear-encoded mitochondrial proteins have been reported to cause tubulointerstitial kidney diseases and focal segmental glomerulosclerosis (FSGS). Recently, genes and pathways affecting mitochondrial turnover and permeability have been implicated in adult-onset FSGS. Furthermore, dysfunctioning mitochondria may be capable of engaging intracellular innate immune-sensing pathways. To determine the impact of mitochondrial dysfunction in FSGS and secondary innate immune responses, we generated Cre/loxP transgenic mice to generate a loss-of-function deletion mutation of the complex IV assembly cofactor heme A:farnesyltransferase (COX10) restricted to cells of the developing nephrons. These mice develop severe, early-onset FSGS with innate immune activation and die prematurely with kidney failure. Mutant kidneys showed loss of glomerular and tubular epithelial function, epithelial apoptosis, and, in addition, a marked interferon response. In vitro modeling of Cox10 deletion in primary kidney epithelium compromises oxygen consumption, ATP generation, and induces oxidative stress. In addition, loss of Cox10 triggers a selective interferon response, which may be caused by the leak of mitochondrial DNA into the cytosol activating the intracellular DNA sensor, stimulator of interferon genes. This new animal model provides a mechanism to study mitochondrial dysfunction in vivo and demonstrates a direct link between mitochondrial dysfunction and intracellular innate immune response. Focal segmental glomerulosclerosis (FSGS) is a pathologic diagnosis made in the setting of proteinuric kidney disease. It is characterized by initial disease of podocytes of the glomerular tuft, frequently associated with tubulointerstitial disease, which is most often proportionate to the severity of glomerular disease. Several mutations in causal genes have been identified in familial FSGS, including those coding for structural proteins of the slit diaphragm of the podocyte.1Lowik M.M. Groenen P.J. Levtchenko E.N. Monnens L.A. van den Heuvel L.P. Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis: a review.Eur J Pediatr. 2009; 168: 1291-1304Crossref PubMed Scopus (96) Google Scholar Nevertheless, most patients do not have a recognized mutation that causes disease, and, in some circumstances, FSGS may be an adaptive manifestation to hyperfiltration. During the past 15 years, case reports have suggested mutations of mitochondrial DNA (mtDNA) may cause several familial and sporadic cases of FSGS, as well as tubular diseases, such as Fanconi syndrome and tubulointerstitial nephritis. Rarely, nuclear genes coding for mitochondrial proteins have been implicated, but these reports have often described kidney disease in the setting of systemic disorders, pointing to widespread mitochondrial disease.2Dinour D. Mini S. Polak-Charcon S. Lotan D. Holtzman E.J. Progressive nephropathy associated with mitochondrial tRNA gene mutation.Clin Nephrol. 2004; 62: 149-154Crossref PubMed Google Scholar, 3Finsterer J. Mitochondriopathies.Eur J Neurol. 2004; 11: 163-186Crossref PubMed Scopus (202) Google Scholar, 4Niaudet P. Rotig A. The kidney in mitochondrial cytopathies.Kidney Int. 1997; 51: 1000-1007Abstract Full Text PDF PubMed Scopus (80) Google Scholar In addition, xenobiotics to treat viral infections and malignancies have been proposed to directly damage mitochondria, causing tubulointerstitial disease. Recently, polymorphisms in an innate immune protein, apolipoprotein L1 (APOL1), have been found to be associated with high risk of developing FSGS in patients of African ancestry, and potentially playing a causative role in a much larger fraction of patients who present with proteinuric progressive kidney disease.5Genovese G. Friedman D.J. Ross M.D. Lecordier L. Uzureau P. Freedman B.I. Bowden D.W. Langefeld C.D. Oleksyk T.K. Uscinski Knob A.L. Bernhardy A.J. Hicks P.J. Nelson G.W. Vanhollebeke B. Winkler C.A. Kopp J.B. Pays E. Pollak M.R. Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1402) Google Scholar Biochemical and cell-based studies suggest intracellular, not circulating, APOL1 may directly disrupt the mitochondrial transmembrane potential in podocytes, to cause podocyte dysfunction.6Vanwalleghem G. Fontaine F. Lecordier L. Tebabi P. Klewe K. Nolan D.P. Yamaryo-Botte Y. Botte C. Kremer A. Burkard G.S. Rassow J. Roditi I. Perez-Morga D. Pays E. Coupling of lysosomal and mitochondrial membrane permeabilization in trypanolysis by APOL1.Nat Commun. 2015; 6: 8078Crossref PubMed Scopus (76) Google Scholar, 7Ma L. Chou J.W. Snipes J.A. Bharadwaj M.S. Craddock A.L. Cheng D. Weckerle A. Petrovic S. Hicks P.J. Hemal A.K. Hawkins G.A. Miller L.D. Molina A.J. Langefeld C.D. Murea M. Parks J.S. Freedman B.I. APOL1 renal-risk variants induce mitochondrial dysfunction.J Am Soc Nephrol. 2017; 28: 1093-1105Crossref PubMed Scopus (84) Google Scholar In addition, disruption or dysfunction of mitochondrial turnover by loss of mitochondrial quality control (mitophagy) has been demonstrated to directly cause FSGS in patients and animal models.8Brown E.J. Schlondorff J.S. Becker D.J. Tsukaguchi H. Tonna S.J. Uscinski A.L. Higgs H.N. Henderson J.M. Pollak M.R. Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis.Nat Genet. 2010; 42: 72-76Crossref PubMed Scopus (340) Google Scholar, 9Kawakami T. Gomez I.G. Ren S. Hudkins K. Roach A. Alpers C.E. Shankland S.J. D'Agati V.D. Duffield J.S. Deficient autophagy results in mitochondrial dysfunction and FSGS.J Am Soc Nephrol. 2015; 26: 1040-1052Crossref PubMed Scopus (116) Google Scholar Such studies strongly implicate mitochondrial dysfunction in the pathogenesis of proteinuric kidney diseases.10Bhargava P. Schnellmann R.G. Mitochondrial energetics in the kidney.Nat Rev Nephrol. 2017; 13: 629-646Crossref PubMed Scopus (510) Google Scholar, 11Che R. Yuan Y. Huang S. Zhang A. Mitochondrial dysfunction in the pathophysiology of renal diseases.Am J Physiol Ren Physiol. 2014; 306: F367-F378Crossref PubMed Scopus (268) Google Scholar Moreover, single-nucleotide polymorphisms in the regulatory sequences of the energy sensor and mitochondrial regulator, AMP-activated protein kinase (PPKAG2), and other mitochondrial metabolism genes, such as carbamoyl phosphate synthase I (CPS1) and glucokinase regulator (GCKR), have been implicated in hypertensive and diabetic kidney diseases with proteinuria from highly powered genome-wide association studies.12Kottgen A. Glazer N.L. Dehghan A. Hwang S.J. Katz R. Li M. et al.Multiple loci associated with indices of renal function and chronic kidney disease.Nat Genet. 2009; 41: 712-717Crossref PubMed Scopus (476) Google Scholar Several mechanisms by which mitochondrial dysfunction can result in FSGS have been reported.13Hagiwara M. Yamagata K. Capaldi R.A. Koyama A. Mitochondrial dysfunction in focal segmental glomerulosclerosis of puromycin aminonucleoside nephrosis.Kidney Int. 2006; 69: 1146-1152Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 14Lim K. Steele D. Fenves A. Thadhani R. Heher E. Karaa A. Focal segmental glomerulosclerosis associated with mitochondrial disease.Clin Nephrol Case Stud. 2017; 5: 20-25Crossref Google Scholar, 15Park E. Kang H.G. Choi Y.H. Lee K.B. Moon K.C. Jeong H.J. Nagata M. Cheong H.I. Focal segmental glomerulosclerosis and medullary nephrocalcinosis in children with ADCK4 mutations.Pediatr Nephrol. 2017; 32: 1547-1554Crossref PubMed Scopus (23) Google Scholar, 16Alcubilla-Prats P. Sole M. Botey A. Grau J.M. Garrabou G. Poch E. Kidney involvement in MELAS syndrome: description of 2 cases.Med Clin (Barc). 2017; 148: 357-361Crossref PubMed Scopus (8) Google Scholar, 17Park E. Ahn Y.H. Kang H.G. Yoo K.H. Won N.H. Lee K.B. Moon K.C. Seong M.W. Gwon T.R. Park S.S. Cheong H.I. COQ6 mutations in children with steroid-resistant focal segmental glomerulosclerosis and sensorineural hearing loss.Am J Kidney Dis. 2017; 70: 139-144Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 18Korkmaz E. Lipska-Zietkiewicz B.S. Boyer O. Gribouval O. Fourrage C. Tabatabaei M. Schnaidt S. Gucer S. Kaymaz F. Arici M. Dinckan A. Mir S. Bayazit A.K. Emre S. Balat A. Rees L. Shroff R. Bergmann C. Mourani C. Antignac C. Ozaltin F. Schaefer F. PodoNet ConsortiumADCK4-associated glomerulopathy causes adolescence-onset FSGS.J Am Soc Nephrol. 2016; 27: 63-68Crossref PubMed Scopus (63) Google Scholar Mitochondrial disease causes increased intracellular reactive oxygen species generation. In certain circumstances, oxidative damage to local organelles, including endoplasmic reticulum and DNA, can occur, although the absolute importance of mitochondrial reactive oxygen species to disease remains unclear. Impaired clearance of defective mitochondrial components, known as mitophagy, also leads to enlarged mitochondria generating reduced ATP and enhanced reactive oxygen species. A reduction in oxidative phosphorylation can compromise cellular function, particularly in cells that rely heavily on mitochondria for ATP generation, including podocytes and epithelium of the kidney. Mitochondria have many functions in addition to metabolism and oxidative phosphorylation. They are critical in detoxification, iron-sulfur cluster biogenesis, intracellular calcium regulation, and central regulation of cell death/survival pathways, including caspase-mediated apoptosis. In addition, mitochondria have been shown to be important sensors and structural regulators of intracellular innate immune responses to pathogens.19Arnoult D. Soares F. Tattoli I. Girardin S.E. Mitochondria in innate immunity.EMBO Rep. 2011; 12: 901-910Crossref PubMed Scopus (181) Google Scholar, 20West A.P. Khoury-Hanold W. Staron M. Tal M.C. Pineda C.M. Lang S.M. Bestwick M. Duguay B.A. Raimundo N. MacDuff D.A. Kaech S.M. Smiley J.R. Means R.E. Iwasaki A. Shadel G.S. Mitochondrial DNA stress primes the antiviral innate immune response.Nature. 2015; 520: 553-557Crossref PubMed Scopus (89) Google Scholar, 21White M.J. McArthur K. Metcalf D. Lane R.M. Cambier J.C. Herold M.J. van Delft M.F. Bedoui S. Lessene G. Ritchie M.E. Huang D.C. Kile B.T. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production.Cell. 2014; 159: 1549-1562Abstract Full Text Full Text PDF PubMed Scopus (528) Google Scholar, 22Gutteridge J.M. Free radicals in disease processes: a compilation of cause and consequence.Free Radic Res Commun. 1993; 19: 141-158Crossref PubMed Scopus (555) Google Scholar, 23Ray P.D. Huang B.W. Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling.Cell Signal. 2012; 24: 981-990Crossref PubMed Scopus (2799) Google Scholar, 24Holmstrom K.M. Finkel T. Cellular mechanisms and physiological consequences of redox-dependent signalling.Nat Rev Mol Cell Biol. 2014; 15: 411-421Crossref PubMed Scopus (1290) Google Scholar Some of the intracellular sensors used to detect intracellular pathogens include the retinoic acid–inducible gene-I–like proteins, stimulator of interferon genes (STING), mitochondrial antiviral signaling protein, cyclic GMP-AMP synthase, and interferon-γ–inducible protein 16, which sense viral RNA and DNA.19Arnoult D. Soares F. Tattoli I. Girardin S.E. Mitochondria in innate immunity.EMBO Rep. 2011; 12: 901-910Crossref PubMed Scopus (181) Google Scholar, 20West A.P. Khoury-Hanold W. Staron M. Tal M.C. Pineda C.M. Lang S.M. Bestwick M. Duguay B.A. Raimundo N. MacDuff D.A. Kaech S.M. Smiley J.R. Means R.E. Iwasaki A. Shadel G.S. Mitochondrial DNA stress primes the antiviral innate immune response.Nature. 2015; 520: 553-557Crossref PubMed Scopus (89) Google Scholar, 25Chan Y.K. Gack M.U. Viral evasion of intracellular DNA and RNA sensing.Nat Rev Microbiol. 2016; 14: 360-373Crossref PubMed Scopus (288) Google Scholar, 26Sun Q. Sun L. Liu H.H. Chen X. Seth R.B. Forman J. Chen Z.J. The specific and essential role of MAVS in antiviral innate immune responses.Immunity. 2006; 24: 633-642Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar, 27Sun L. Wu J. Du F. Chen X. Chen Z.J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.Science. 2013; 339: 786-791Crossref PubMed Scopus (2508) Google Scholar, 28Ablasser A. Hemmerling I. Schmid-Burgk J.L. Behrendt R. Roers A. Hornung V. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner.J Immunol. 2014; 192: 5993-5997Crossref PubMed Scopus (161) Google Scholar, 29Cai X. Chiu Y.H. Chen Z.J. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling.Mol Cell. 2014; 54: 289-296Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar It has been proposed that the leakage of mtDNA from dysfunctioning or disrupted mitochondria could additionally directly activate STING, the DNA sensor, providing a direct potential link between mitochondrial disease and inflammatory response.20West A.P. Khoury-Hanold W. Staron M. Tal M.C. Pineda C.M. Lang S.M. Bestwick M. Duguay B.A. Raimundo N. MacDuff D.A. Kaech S.M. Smiley J.R. Means R.E. Iwasaki A. Shadel G.S. Mitochondrial DNA stress primes the antiviral innate immune response.Nature. 2015; 520: 553-557Crossref PubMed Scopus (89) Google Scholar, 30West A.P. Mitochondrial dysfunction as a trigger of innate immune responses and inflammation.Toxicology. 2017; 391: 54-63Crossref PubMed Scopus (106) Google Scholar However, abundant extracellular mtDNA can be found in tissue injury but does not activate toll-like receptors that sense extracellular foreign DNA, except in rare circumstances in which the DNA is reported to be highly oxidized.31Lood C. Blanco L.P. Purmalek M.M. Carmona-Rivera C. De Ravin S.S. Smith C.K. Malech H.L. Ledbetter J.A. Elkon K.B. Kaplan M.J. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease.Nat Med. 2016; 22: 146-153Crossref PubMed Scopus (810) Google Scholar Therefore, the role of mtDNA leakage in innate immune responses and its contribution to pathogenesis in the setting of noninfectious kidney disease are unexplored. In the following studies, we validated the hypothesis that mutation of a single gene that contributes to complex IV (COX-IV) stability in the electron transport chain is sufficient to cause the pathologic manifestations of FSGS and determined in a controlled manner whether mutation-driven mitochondrial dysfunction directly activates sensors of viral DNA sufficient to trigger an interferon response. To this end, nephron-specific complex IV assembly cofactor heme A:farnesyltransferase (Cox10) conditional knockout mice (Cox10fl/fl)32Diaz F. Thomas C.K. Garcia S. Hernandez D. Moraes C.T. Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency.Hum Mol Genet. 2005; 14: 2737-2748Crossref PubMed Scopus (126) Google Scholar expressing Cre under the control of the Six2 promotor (Six2-Cre+;Cox10fl/fl:Cox10Δ/Δ) were generated. The nephron is the structural and functional unit involved in all key processes, including filtration, reabsorption, secretion, and excretion. In bigenic, homozygous, floxed mice, Cox10 was disrupted in Six2-expressing nephron progenitors and their progeny, which form the mesenchyme-derived kidney epithelium, including podocytes, parietal epithelial cells, proximal tubules, loops of Henle, and distal tubules.33Humphreys B.D. Valerius M.T. Kobayashi A. Mugford J.W. Soeung S. Duffield J.S. McMahon A.P. Bonventre J.V. Intrinsic epithelial cells repair the kidney after injury.Cell Stem Cell. 2008; 2: 284-291Abstract Full Text Full Text PDF PubMed Scopus (678) Google Scholar, 34Kobayashi A. Valerius M.T. Mugford J.W. Carroll T.J. Self M. Oliver G. McMahon A.P. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development.Cell Stem Cell. 2008; 3: 169-181Abstract Full Text Full Text PDF PubMed Scopus (697) Google Scholar Cox10 encodes a heme A/farnesyl transferase,35Tzagoloff A. Nobrega M. Gorman N. Sinclair P. On the functions of the yeast COX10 and COX11 gene products.Biochem Mol Biol Int. 1993; 31: 593-598PubMed Google Scholar which is required for the correct assembly of cytochrome c oxidase (COX-IV; alias the complex IV of the electron transport chain), a critical complex in mitochondrial respiratory ATP production.36Diaz F. Cytochrome c oxidase deficiency: patients and animal models.Biochim Biophys Acta. 2010; 1802: 100-110Crossref PubMed Scopus (101) Google Scholar Genetic deletion of Cox10 causes COX-IV deficiency, in turn leading to mitochondrial dysfunction.32Diaz F. Thomas C.K. Garcia S. Hernandez D. Moraes C.T. Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency.Hum Mol Genet. 2005; 14: 2737-2748Crossref PubMed Scopus (126) Google Scholar, 37Fukui H. Diaz F. Garcia S. Moraes C.T. Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease.Proc Natl Acad Sci U S A. 2007; 104: 14163-14168Crossref PubMed Scopus (146) Google Scholar, 38Hatakeyama H. Goto Y.I. Respiratory chain complex disorganization impairs mitochondrial and cellular integrity: phenotypic variation in cytochrome c oxidase deficiency.Am J Pathol. 2017; 187: 110-121Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Mice harboring loxP-flanked Cox10 alleles32Diaz F. Thomas C.K. Garcia S. Hernandez D. Moraes C.T. Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency.Hum Mol Genet. 2005; 14: 2737-2748Crossref PubMed Scopus (126) Google Scholar were crossed to a mouse strain expressing Cre under the Six2 promotor to generate nephron-specific Cox10 conditional knockout mice (Six2-Cre+;Cox10fl/fl:Cox10Δ/Δ) and the littermate controls carrying either unexcised floxed or Cox10 wild-type (WT) gene on both alleles (Cox10+/+). To test prenatal lethality of Cox10Δ/Δ mice, Six2-Cre−/−;Cox10fl/fl mice were bred with Six2-Cre+/−;Cox10fl/+. Studies were performed under approved Institutional Animal Care and Use Committee protocols (0489-2013 and 755) at Biogen Inc. (Cambridge, MA) and the University of Washington (Seattle, WA; protocol 4244).39Committee for the Update of the Guide for the Care and Use of Laboratory AnimalsNational Research CouncilGuide for the Care and Use of Laboratory Animals: Eighth Edition. National Academies Press, Washington, DC2011Crossref Google Scholar Kidneys were resected after systemic perfusion with ice-cold phosphate-buffered saline (PBS). Paraffin-embedded sections of kidney fixed with neutral-buffered formalin were used for periodic acid-Schiff, methenamine silver, and picrosirius red staining, as described previously.9Kawakami T. Gomez I.G. Ren S. Hudkins K. Roach A. Alpers C.E. Shankland S.J. D'Agati V.D. Duffield J.S. Deficient autophagy results in mitochondrial dysfunction and FSGS.J Am Soc Nephrol. 2015; 26: 1040-1052Crossref PubMed Scopus (116) Google Scholar Glomerular pathology was evaluated by an observer-blinded pathologist (Y.W.) assessing all glomeruli of whole cortex of a sagittal section of the whole kidney from each mouse (×40 magnification) in periodic acid-Schiff– or methenamine silver–stained kidney sections, as described in several previous publications.9Kawakami T. Gomez I.G. Ren S. Hudkins K. Roach A. Alpers C.E. Shankland S.J. D'Agati V.D. Duffield J.S. Deficient autophagy results in mitochondrial dysfunction and FSGS.J Am Soc Nephrol. 2015; 26: 1040-1052Crossref PubMed Scopus (116) Google Scholar, 40Nakagawa N. Barron L. Gomez I.G. Johnson B.G. Roach A.M. Kameoka S. Jack R.M. Lupher Jr., M.L. Gharib S.A. Duffield J.S. Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease.JCI Insight. 2016; 1: e87446Crossref PubMed Scopus (33) Google Scholar, 41Ma L.J. Fogo A.B. Model of robust induction of glomerulosclerosis in mice: importance of genetic background.Kidney Int. 2003; 64: 350-355Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar Between 42 and 71 glomeruli were scored sequentially per animal. Each glomerular section was quantified for the percentage of sclerotic glomeruli (capillary loop obliteration and replacement with sclerotic matrix). Up to 25% of tuft involved scored 1, up to 50% of tuft scored 2, up to 75% of tuft scored 3, and up to 100% of tuft scored 4. Visceral epithelial cell hyperplasia with collapsing-type lesions (pseudocrescents) was defined as more than two layers of epithelial cells with the parietal basement membrane. Tubular pathology was evaluated by assessing 10 randomly selected microscopic fields (×10 magnification) of the outer medulla per animal in periodic acid-Schiff–stained kidney sections and determining the numbers of dilated, atrophic tubules and tubules with casts. The protocol for tissue preparation and staining for transmission electron microscopy has been described previously.42Li B. Castano A.P. Hudson T.E. Nowlin B.T. Lin S.L. Bonventre J.V. Swanson K.D. Duffield J.S. The melanoma-associated transmembrane glycoprotein Gpnmb controls trafficking of cellular debris for degradation and is essential for tissue repair.FASEB J. 2010; 24: 4767-4781Crossref PubMed Scopus (106) Google Scholar Grids were scanned using a JEM-1380 electron microscope (Jeol, Peabody, MA). Serum and urinary creatinine were measured using Creatinine Liquid Reagents Assay (Diazyme, San Diego, CA) or a urinary creatinine detection kit (Thermo Fisher Scientific, Carlsbad, CA). Blood urea nitrogen levels were detected by blood urea nitrogen (Pointe Scientific, Canton, MI). Urinary albumin concentration was measured using an Albuwell M kit (Exocell, Philadelphia, PA). Kidneys were fixed with periodate-lysine-paraformaldehyde fixative. After immersion in PBS, including 18% sucrose at 4°C overnight, they were embedded and frozen in optimal cutting temperature compound (Sakura Finetek, Torrance, CA). Cryostat-cut mouse kidney sections (5 μm thick) were stained for the following: fibrosis, using Cy3-conjugated anti–α-smooth muscle actin antibody (Ab;; 1:200; clone 1A4; Sigma-Aldrich, St. Louis, MO); tubular injury, using polyclonal rabbit anti-human kidney injury molecule-1 Ab (1:200; catalog ab47635; Abcam, Cambridge, MA); apoptosis, using rabbit anti-human cleaved caspase-3 Ab (1:50; clone 5A1E; Cell Signaling Technology, Danvers, MA); proximal tubules, using fluorescein isothiocyanate–conjugated lotus tetragonolobus lectin (LTL; 1:200; catalog FL-1321; Vector Laboratories, Burlingame, CA); and macrophages, using rat anti-mouse F4/80 Ab (1:400; clone BM-8; Thermo Fisher Scientific). This was followed by Cy3-conjugated donkey anti-rabbit IgG Ab, Alexa Fluor 488 donkey anti-rabbit IgG antibody, and Cy3-conjugated donkey anti-rat IgG Ab (1:400; Jackson ImmunoResearch, West Grove, PA). All sections were mounted with mounting medium containing 4′,6-diamidino-2-phenylindole (DAPI; catalog P36931; Thermo Fisher Scientific). Images were taken using an LSM 710 laser-scanning confocal microscope (Zeiss, Thornwood, NY). The magnitude of staining was analyzed in 10 microscopic fields per animal using Adobe Photoshop CC 2017 (Adobe Systems, San Jose, CA). SDS-PAGE and Western blot analysis were performed as described previously.9Kawakami T. Gomez I.G. Ren S. Hudkins K. Roach A. Alpers C.E. Shankland S.J. D'Agati V.D. Duffield J.S. Deficient autophagy results in mitochondrial dysfunction and FSGS.J Am Soc Nephrol. 2015; 26: 1040-1052Crossref PubMed Scopus (116) Google Scholar, 43Baek J.H. Birchmeier C. Zenke M. Hieronymus T. The HGF receptor/Met tyrosine kinase is a key regulator of dendritic cell migration in skin immunity.J Immunol. 2012; 189: 1699-1707Crossref PubMed Scopus (59) Google Scholar To detect total and phosphorylated STING, protein electrophoresis was performed using 7.5% SuperSep Phos-tag gel (Wako, Richmond, VA). Primary antibodies used were as follows: polyclonal rabbit anti-cytochrome c oxidase subunit I (COX1; 1:1000; catalog PA5-26688; Thermo Fisher Scientific), rabbit anti-COX10 (1:1000; catalog MBS2526567; MyBiosource Inc., San Diego, CA), monoclonal rabbit anti-interferon regulatory factor 1 (IRF1; 1:1000; clone D5E4; Cell Signaling Technology), rabbit anti–2′-5′-oligoadenylate synthase 1 (OAS1; 1:1000; clone D1W3A; Cell Signaling Technology), rabbit anti-STAT3 (1:1000; clone 79D7; Cell Signaling Technology), rabbit anti-STING (1:1000; clone D1V5L; Cell Signaling Technology), rabbit anti–TRAF family member-associated NFkappaB activator (TANK)-binding kinase-1 [TBK1; 1:2000; clone EPR2867(2)-19; Abcam], rabbit anti–phosphorylated TBK1 (1:250; clone D52C2; Cell Signaling Technology), and mouse anti–glyceraldehyde-3-phosphate dehydrogenase Ab (1:2000; clone GT239; GeneTex, Irvine, CA). Total RNA was extracted from kidney biopsy specimens from Cox10Δ/Δ and Cox10+/+ mice using RNeasy Plus Mini Kit (Qiagen, Hilden, Germany). Purity was determined by measuring the 260/280 and 260/239 ratio. Gene expression profiling was performed using next-generation sequencing on the Illumina HiSeq 2500 platform producing 50-bp paired-end reads. Total reads were mapped using the aligner STAR.44Dobin A. Davis C.A. Schlesinger F. Drenkow J. Zaleski C. Jha S. Batut P. Chaisson M. Gingeras T.R. STAR: ultrafast universal RNA-seq aligner.Bioinformatics. 2013; 29: 15-21Crossref PubMed Scopus (19157) Google Scholar Genes were quantified with RSEM,45Li B. Dewey C.N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome.BMC Bioinformatics. 2011; 12: 323Crossref PubMed Scopus (10800) Google Scholar and differential expression was determined by DESeq2 using Array Studio 10 (OmicSoft, Cary, NC).46Love M.I. Huber W. Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.Genome Biol. 2014; 15: 550Crossref PubMed Scopus (32370) Google Scholar Significantly differentially expressed genes were selected according to the following criteria: false discovery rate–corrected P < 0.001 and fold change >1.4-fold. Analysis was subjected to the enrichment test for gene ontology and pathway analysis through the use of Ingenuity Pathway Analysis version 01-1047Kramer A. Green J. Pollard Jr., J. Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis.Bioinformatics. 2014; 30: 523-530Crossref PubMed Scopus (2771) Google Scholar (Qiagen) or DAVID version 6.8 (http://david.ncifcrf.gov).48Huang D.W. Sherman B.T. Lempicki R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.Nature Protoc. 2009; 4: 44-57Crossref PubMed Scopus (25346) Google Scholar, 49Huang D.W. Sherman B.T. Lempicki R.A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists.Nucleic Acids Res. 2009; 37: 1-13Crossref PubMed Scopus (10271) Google Scholar Differentially expressed genes were subjected to functional protein association analysis using STRING database version 10.5 (http://www.string-db.org, last accessed March 16, 2018, registration required). Differentially expressed genes were interferon-stimulated genes (ISGs) and were identified using the online database INTERFEROME version 2.01 (http://www.interferome.org/interferome/home.jspx, last accessed March 19, 2018). Because the RNA was directly sequenced, PCR confirmation of transcriptional changes was not considered necessary. All RNA sequencing data and expression values are available at the Gene Expression Omnibus repository at the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/geo; accession number GSE117681). Kidneys from WT mice at 2 to 3 months of age were harvested, decapsulated, diced, and then incubated at 37°C for 60 minutes with liberase thermolysin low (0.2 mg/mL; Roche, Indianapolis, IN) in the presence of DNase I (100 U/mL) in serum-free Dulbecco's modified Eagle's medium/F12 medium. After filtration (40 μm), proximal tubular epithelial cells (PTECs) were enriched usi" @default.
• W2894198112 created "2018-10-05" @default.
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• W2894198112 date "2018-12-01" @default.
• W2894198112 modified "2023-10-10" @default.
• W2894198112 title "Deletion of the Mitochondrial Complex-IV Cofactor Heme A:Farnesyltransferase Causes Focal Segmental Glomerulosclerosis and Interferon Response" @default.
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