Molecular events in matrix protein metabolism in the aging kidney

Summary We explored molecular events associated with aging‐induced matrix changes in the kidney. C 57 BL 6 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 m RNA varied with the phase of aging. The content of ZEB 1 and ZEB 2, collagen type I transcription inhibitors, and their binding to the collagen type I α2 promoter by C h IP assay also showed age‐phase‐specific changes. Lack of increase in m RNA 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 TGF β m RNA and protein and activation of its SMAD 3 pathway; SMAD 3 binding to the collagen type I α2 promoter was also increased. TGF β‐regulated micro RNA s (mi R s) exhibited selective regulation. The renal cortical content of mi R ‐21 and mi R ‐200c, but not mi R ‐192, mi R ‐200a, or mi R ‐200b, was increased with aging. Increased mi R ‐21 and mi R ‐200c contents were associated with reduced expression of their targets, S prouty‐1 and ZEB 2, 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.