Molecular events in matrix protein metabolism in the aging kidney

• Published in: Aging cell Vol. 11; no. 6; pp. 1065 - 1073
• Main Authors: Sataranatarajan, Kavithalakshmi, Feliers, Denis, Mariappan, Meenalakshmi M., Lee, Hak Joo, Lee, Myung Ja, Day, Robert T., Yalamanchili, Hima Bindu, Choudhury, Goutam G., Barnes, Jeffrey L., Remmen, Holly, Richardson, Arlan, Kasinath, Balakuntalam S.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2012
• Subjects: Adaptor Proteins, Signal Transducing; Age; Aging; Aging - genetics; Aging - metabolism; Aging - pathology; albuminuria; Animals; Collagen; Collagen Type I - genetics; Collagen Type I - metabolism; Collagen Type III - genetics; Collagen Type III - metabolism; Cystatin C - blood; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Female; fibrosis; Gene Expression Regulation, Developmental; Glomerular Filtration Rate; Glomerular Mesangium - metabolism; Glomerular Mesangium - pathology; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Kidney Cortex - metabolism; Kidney Cortex - pathology; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; microRNAs; MicroRNAs - genetics; Phosphoproteins - genetics; Phosphoproteins - metabolism; Promoter Regions, Genetic; Protein Binding; Proteins; Proteolysis; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA, Messenger - biosynthesis; Serum Albumin - metabolism; SMAD3; Smad3 Protein - genetics; Smad3 Protein - metabolism; TGF beta; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Zinc Finger E-box Binding Homeobox 2; Zinc Finger E-box-Binding Homeobox 1
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12008

Summary 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.