Tretinoin Prevents Age-Related Renal Changes and Stimulates Antioxidant Defenses in Cultured Renal Mesangial Cells

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 289; no. 1; pp. 123 - 132
• Main Authors: Manzano, V. Moreno, Puyol, M. Rodriguez, Puyol, D. Rodriguez, Cazaña, F. J.Lucio
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.04.1999
• Subjects: Aging - pathology; Animals; Antioxidants - metabolism; Catalase - biosynthesis; Cell Survival - drug effects; Cells, Cultured; Cytokines - biosynthesis; Diet; Glomerular Mesangium - drug effects; Glomerular Mesangium - metabolism; Glomerular Mesangium - pathology; Glutathione - metabolism; Humans; Hydrogen Peroxide - antagonists & inhibitors; Kidney Cortex - drug effects; Kidney Cortex - pathology; Male; Osteopontin; Oxidants - antagonists & inhibitors; Rats; Rats, Inbred F344; RNA, Messenger - biosynthesis; Sialoglycoproteins - biosynthesis; Transforming Growth Factor beta - biosynthesis; Tretinoin - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1016/s0022-3565(24)38114-5

Age-related progressive glomerular sclerosis in the rat is associated with increased expression of tumor necrosis factor-β 1 and increased protein content in the renal cortex, enhanced production of H 2 O 2 , in both renal glomeruli and mesangial cells (MCs) cultured from them, as well as augmented glomerular oxidative damage. We have previously shown that tretinoin-treated old male Fischer 344 rats have 30% lower protein content in the renal cortex than control old rats. Here, we report that this effect may depend on the inhibition of the expression of tumor necrosis factor-β 1 , a matrigenic cytokine, and osteopontin, a protein with cell adhesive and chemotactic properties. In addition, we show that tretinoin prevents the cytotoxicity of H 2 O 2 in cultured human MCs by increasing both the catalase activity and the reduced glutathione content, which are dose- and time-dependent changes. These increases were not dependent on each other: when these effects were previously inhibited with 3-amino-1,2,4-atriazole or l -buthionine-( S , R )-sulfoximine, respectively, tretinoin still induced the increase of the other noninhibited antioxidant defense. An enhanced gene transcription is the most likely mechanism involved in the tretinoin-induced stimulation of MC antioxidant defense systems because 1) preincubation of MCs with actinomycin D or cycloheximide fully abolished it; 2) tretinoin-incubated MCs showed increased levels of catalase mRNA and γ-glutamyl-cysteine synthetase (catalytic subunit) mRNA, the latter being the rate-limiting step in de novo reduced glutathione synthesis; and 3) the stability of both mRNA was unchanged by tretinoin. These results show one strategy of protecting renal cells from H 2 O 2 -mediated injury based on increasing their antioxidant defenses.