Glomerular dysfunction in the aging Fischer 344 rat is associated with excessive growth and normal mesangial cell function

Background. Fischer 344 (F344) rats display focal and diffuse glomerulosclerosis with aging postulated to result from loss of normal mesangial cell intrinsic function, e.g., vasoactive hormone signaling, or preservation of normal responsiveness to extrinsic growth factors. Methods. In 3-, 17-, and 24-month-old F344 male rats, glomerular structure, measured by PC-based morphometry, and function were compared. Immunoperoxidase staining of glomerular proliferating cell nuclear antigen (PCNA) detected cellular proliferation. Primary cultured mesangial cells from the 3 age groups were studied in parallel. Calcium (Ca²⁺) signaling, measured by Fura-2 fluorescence, contraction to vasopressin (AVP) 1 μM, measured by videomicroscopy, and proliferative response to platelet-derived growth factor-ββ (PDGF) were compared. Results. Proteinuria was 13 ± 4, 38 ± 17, and 110 ± 35 mg/24 hours at 3, 17, and 24 months, respectively (n = 5, mean ± SE, p < 01, 3 vs 24 months), with no change in 24-hour creatinine clearances. Glomerular volumes (n = 200/group) for 3, 17, and 24 months, respectively, were .30 ± .01, .60 ± .02, .74 ± .02 x 10⁶ μm³ (p < .001, 3 months vs 17 months, and 17 vs 24 months). Glomerular basement membrane (GBM) widths and fractional mesangial volumes increased significantly with aging. Glomerular cell PCNA staining remained positive at 24 months. Cultured mesangial cell Ca²⁺ signaling and contraction to AVP were unchanged with aging. Proliferation to PDGF, which was partially inhibited with verapamil, was similar at 3 and 24 months. Conclusions. In the Fischer 344 rat, mesangial cell Ca²⁺ signaling, contraction, and proliferation responsiveness are unchanged with aging. Continued growth is associated with the glomerulosclerosis of aging.