title: Molecular events in matrix protein metabolism in the aging kidney.
abstract: We explored molecular events associated with aging-induced matrix changes in the kidney. C57BL6 mice were studied in youth, middle age, and old age. Albuminuria and serum cystatin C level (an index of glomerular filtration) increased with aging. Renal hypertrophy was evident in middle-aged and old mice and was associated with glomerulomegaly and increase in mesangial fraction occupied by extracellular matrix. Content of collagen types I and III and fibronectin was increased with aging; increment in their mRNA varied with the phase of aging. The content of ZEB1 and ZEB2, collagen type I transcription inhibitors, and their binding to the collagen type Iα2 promoter by ChIP assay also showed age-phase-specific changes. Lack of increase in mRNA and data from polysome assay suggested decreased degradation as a potential mechanism for kidney collagen type I accumulation in the middle-aged mice. These changes occurred with increment in TGFβ mRNA and protein and activation of its SMAD3 pathway; SMAD3 binding to the collagen type Iα2 promoter was also increased. TGFβ-regulated microRNAs (miRs) exhibited selective regulation. The renal cortical content of miR-21 and miR-200c, but not miR-192, miR-200a, or miR-200b, was increased with aging. Increased miR-21 and miR-200c contents were associated with reduced expression of their targets, Sprouty-1 and ZEB2, respectively. These data show that aging is associated with complex molecular events in the kidney that are already evident in the middle age and progress to old age. Age-phase-specific regulation of matrix protein synthesis occurs and involves matrix protein-specific transcriptional and post-transcriptional mechanisms.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Kavithalakshmi
authors.initials: K
authors.lastname: Sataranatarajan
authors.forename: Denis
authors.initials: D
authors.lastname: Feliers
authors.forename: Meenalakshmi M
authors.initials: MM
authors.lastname: Mariappan
authors.forename: Hak Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Myung Ja
authors.initials: MJ
authors.lastname: Lee
authors.forename: Robert T
authors.initials: RT
authors.lastname: Day
authors.forename: Hima Bindu
authors.initials: HB
authors.lastname: Yalamanchili
authors.forename: Goutam G
authors.initials: GG
authors.lastname: Choudhury
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Barnes
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D055316:Cystatin C / Q000097:blood; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005919:Glomerular Filtration Rate; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007672:Kidney Cortex / Q000378:metabolism* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D059748:Proteolysis; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D024042:Collagen Type I; D024061:Collagen Type III; D055316:Cystatin C; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D035683:MicroRNAs; D010750:Phosphoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D012709:Serum Albumin; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C425468:Spry1 protein, mouse; D016212:Transforming Growth Factor beta; C519422:ZEB1 protein, mouse; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1