Age-Dependent Expression of Fibrosis-Related Genes and Collagen Deposition in Rat Kidney Cortex

Abstract

Because progressive fibrosis is a histological hallmark of the aging kidney, we sought to characterize the course of some fibrosis-related genes [pro-alpha2(I)collagen (COL-I), pro-alpha1(III)collagen (COL-III), and transforming growth factors beta1 and beta3 (TGF-beta1 and TGF-beta3)] of interstitial collagen accumulation [COL-I and COL-III proteins, hydroxyproline (PRO-OH), histology] and its degradation (matrix metalloproteinase MMP-1 and -2) during maturation and early aging in rats. During the lifespan considered we observed no changes in the mRNA, except that COL-I mRNA tended to be up-regulated from 2 to 19 months of age. However, progressive fibrosis was histologically detectable, with COL-I accumulation (p < .05 and p < .01 in 12-month- and 19-month-old rats vs the youngest), and confirmed by the PRO-OH tissue levels (p = .0001); COL-III seemed to be less involved. The MMP-1 protein level decreased significantly in the cortex of 12-month- and 19-month-old rats (p < .05), whereas MMP-2 protein level and activity remained essentially unchanged. These results show that, during aging of the kidney, (i) renal cortex fibrosis is explained by COL-I accumulation as a consequence of an altered balance between its synthesis and degradation, and (ii) the expression of the pleiotropic factor TGF-beta in the renal cortex is not modified.

Reduced collagenolytic activity of matrix metalloproteinases and development of liver fibrosis in the aging rat

“…The same situation was described in the heart and in the kidney where the age-related accumulation of interstitial and perivascular COL was not accompanied by significant changes in TGF-b gene expression (Annoni et al, 1997;Gagliano et al, 2000). These data further support the hypothesis that age-dependent organ fibrosclerosis, including the liver, is unrelated to the significant of TGF-b.…”

“…Fibrosis is a hallmark of the aging of various organs, including the heart and kidney (Abrass et al, 1995;Annoni et al, 1997;Gagliano et al, 2000), and reflects increased deposition of the physiological components of the extracellular matrix (ECM). The liver ECM is not only a passive structural support, since it plays key roles in providing a structural framework and maintaining the differentiated phenotype and normal function of hepatocytes, sinusoidal endothelial and stellate cells (Martinez-Hernandez, 1984;Martinez-Hernandez and Amenta, 1993).…”

Matrix metalloproteinases in kidney homeostasis and diseases

“…The excessive accumulation of ECM in CKD is likely to involve aberrant levels of MMPs/TIMPs. MMP-1 is downregulated in aging kidneys that have collagen deposition (33). TIMP-1 overexpression occurs in fibrosis and can promote fibroblast proliferation independently of MMP inhibition (72).…”

Towards a unified approach in the modeling of fibrosis: A review with research perspectives

“…Since physiological/pathological fibrosis is an age-dependent process [144,145], the applicability of models with internal structure appears suitable. Most existing models with internal structures for fibrosis focus on the repair of the epithelial layer [146] and the remodeling of the fibrotic tissue [147].…”