title: The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age.
abstract: Although age-associated changes in kidney glomerular architecture have been described in mice and man, the mechanisms are unknown. It is unclear if these changes can be prevented or even reversed by systemic therapies administered at advanced age. Using light microscopy and transmission electron microscopy, our results showed glomerulosclerosis with injury to mitochondria in glomerular epithelial cells in mice aged 26 months (equivalent to a 79-year-old human). To test the hypothesis that reducing mitochondrial damage in late age would result in lowered glomerulosclerosis, we administered the mitochondrial targeted peptide, SS-31, to aged mice. Baseline (24-month-old) mice were randomized to receive 8 weeks of SS-31, or saline, and killed at 26 months of age. SS-31 treatment improved age-related mitochondrial morphology and glomerulosclerosis. Assessment of glomeruli revealed that SS-31 reduced senescence (p16, senescence-associated-ß-Gal) and increased the density of parietal epithelial cells. However, SS-31 treatment reduced markers of parietal epithelial cell activation (Collagen IV, pERK1/2, and α-smooth muscle actin). SS-31 did not impact podocyte density, but it reduced markers of podocyte injury (desmin) and improved cytoskeletal integrity (synaptopodin). This was accompanied by higher glomerular endothelial cell density (CD31). Thus, despite initiating therapy in late-age mice, a short course of SS-31 has protective benefits on glomerular mitochondria, accompanied by temporal changes to the glomerular architecture. This systemic pharmacological intervention in old-aged animals limits glomerulosclerosis and senescence, reduces parietal epithelial cell activation, and improves podocyte and endothelial cell integrity.
authors.affiliation: Division of Nephrology, University of Washington, Seattle, WA, USA.
authors.forename: Mariya T
authors.initials: MT
authors.lastname: Sweetwyne
authors.affiliation: Division of Nephrology, University of Washington, Seattle, WA, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pippin
authors.affiliation: Division of Nephrology, University of Washington, Seattle, WA, USA.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Eng
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudkins
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Ying Ann
authors.initials: YA
authors.lastname: Chiao
authors.affiliation: Department of Radiology, University of Washington, Seattle, WA, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Campbell
authors.affiliation: Department of Radiology, University of Washington, Seattle, WA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Marcinek
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.affiliation: Division of Nephrology, University of Washington, Seattle, WA, USA. Electronic address: stuartjs@uw.edu.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Shankland
mesh_terms: D000199:Actins / Q000378:metabolism; D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D050199:Podocytes / Q000187:drug effects; D012598:Sclerosis
chemical_list: D000199:Actins; D024141:Collagen Type IV; D003893:Desmin; D008840:Microfilament Proteins; D009842:Oligopeptides; C503968:Synpo protein, mouse; C544013:alpha-smooth muscle actin, mouse; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: glomerulosclerosis; glomerulus; parietal epithelial cells; podocyte