A dual agonist of farnesoid X receptor (FXR) and the G protein–coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice

• Published in: The Journal of biological chemistry Vol. 292; no. 29; pp. 12018 - 12024
• Main Authors: Wang, Xiaoxin X., Luo, Yuhuan, Wang, Dong, Adorini, Luciano, Pruzanski, Mark, Dobrinskikh, Evgenia, Levi, Moshe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.07.2017; American Society for Biochemistry and Molecular Biology
• Subjects: Accelerated Communications; Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; bile acid; Bile Acids and Salts - pharmacology; Bile Acids and Salts - therapeutic use; Caloric Restriction; Cells, Cultured; Gene Expression Regulation, Developmental; Humans; Hypolipidemic Agents - pharmacology; Hypolipidemic Agents - therapeutic use; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; kidney; Kidney - drug effects; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Longevity; Mice, Inbred C57BL; Mice, Mutant Strains; Mitochondria - enzymology; Mitochondria - immunology; Mitochondria - metabolism; Mitochondria - pathology; mitochondrial metabolism; Mitochondrial Turnover; Podocytes - drug effects; Podocytes - immunology; Podocytes - metabolism; Podocytes - pathology; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Renal Insufficiency - drug therapy; Renal Insufficiency - metabolism; Renal Insufficiency - pathology; Renal Insufficiency - prevention & control; kidney; aging; bile acid; kidney metabolism; mitochondrial metabolism
• DOI: 10.1074/jbc.C117.794982
• ISSN: 0021-9258; 1083-351X

Even in healthy individuals, renal function gradually declines during aging. However, an observed variation in the rate of this decline has raised the possibility of slowing or delaying age-related kidney disease. One of the most successful interventional measures that slows down and delays age-related kidney disease is caloric restriction. We undertook the present studies to search for potential factors that are regulated by caloric restriction and act as caloric restriction mimetics. Based on our prior studies with the bile acid–activated nuclear hormone receptor farnesoid X receptor (FXR) and G protein–coupled membrane receptor TGR5 that demonstrated beneficial effects of FXR and TGR5 activation in the kidney, we reasoned that FXR and TGR5 could be excellent candidates. We therefore determined the effects of aging and caloric restriction on the expression of FXR and TGR5 in the kidney. We found that FXR and TGR5 expression levels are decreased in the aging kidney and that caloric restriction prevents these age-related decreases. Interestingly, in long-lived Ames dwarf mice, renal FXR and TGR5 expression levels were also increased. A 2-month treatment of 22-month-old C57BL/6J mice with the FXR-TGR5 dual agonist INT-767 induced caloric restriction-like effects and reversed age-related increases in proteinuria, podocyte injury, fibronectin accumulation, TGF-β expression, and, most notably, age-related impairments in mitochondrial biogenesis and mitochondrial function. Furthermore, in podocytes cultured in serum obtained from old mice, INT-767 prevented the increases in the proinflammatory markers TNF-α, toll-like receptor 2 (TLR2), and TLR4. In summary, our results indicate that FXR and TGR5 may play an important role in modulation of age-related kidney disease.