Molecular pathways in age-associated chronic renal pathologies
Purpose: The pathogenesis of age-related changes in the kidney such as increased tubulointerstitial fibrosis and tubular atrophy is poorly understood. Oxidative stress and related cellular signaling pathways are implicated. This investigation compared markers of age-related renal pathologies with oxidative stress and cell signalling pathways in kidneys from old rats of varying genetic makeup.
Methods: Kidneys were compared from 2yo male spontaneously hypertensive (SHR, N=4, mean body weight MBW 394+/-26g), normotensive (WKY, N=3, MBW 444+/-31g), Wistar Obese (N=4, MBW 689+/-52g) and young adult rats (YA, N = 4, MBW 200+/-20g). Tissue was prepared for microscopy or Western blots. Markers of pathologies were expression of Bcl-2 and Bax, and serum lactate dehydrogenase (LDH). Fibrosis score (FS), lipofuscin and inflammatory cells were assessed using special stains. HO-1 and signalling molecules likely to alter in ageing (phospho-cav1, mTOR, p66Shc and phospho-p66Shc) were compared.
Results: FS and LDH were highest in old rats, especially with high MBW (FS: SHR 15+/-10, WKY 3.3+/-2.9, Wistar 40+/-24, YA 0; LDH: SHR 3263+/-428, WKY 2660+/-435, Wistar 4100+/-906, YA 653+/-82) (Wistars, p<0.05). mTOR expression was significantly reduced in aged compared with young kidneys. High levels of HO-1 and phospho-cav1 in aged kidneys (Wistars, p<0.05) supported a role for oxidative stress. p66Shc was expressed in all groups, however phospho-p66Shc was significantly increased only in SHR rats (p<0.05). Other molecules showed trends in expression that supported their known roles in disease, but did not reach significance.
Conclusions: Markers of age-associated chronic renal pathologies showed strong links with oxidative stress and obesity.