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

Abstract

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 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 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.

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“…In the early stages of disease, tubular growth can result in an increase in kidney weight (especially the proximal tubule which comprises ∼90% of the renal cortex) and may be associated with poor renal outcome . In addition, primary increases in renal expression of SGLT2 and/or SGLT1 have been observed in diabetic mice . Studies in T2DM patients identified that renal SGLT1 mRNA expression was markedly increased and SGLT2 mRNA levels (not significantly) down‐regulated .…”

Acarbose improves health and lifespan in aging HET3 mice

“…Activating the bile acid‐activated nuclear hormone receptor FXR, and the G protein coupled receptor TGR5, reduces several diseases of aging, including chronic liver and kidney disease as well as diabetes (Rizzo et al, ). Chronic treatment of aging mice with INT‐767d could, in principle, retard these diseases as well as other deleterious aspects of aging (Fiorucci, Mencarelli, Palladino, & Cipriani, ; Hylemon et al, ; Wang et al, ). Dwarf mouse models with increased lifespan also have increased serum and liver bile acid levels and FXR activation, which supports this idea (Gems, ).…”

Clinical Trial Design for Alcoholic Hepatitis

“…The rationale is that activation will improve hepatic recirculation of bile acids, reduce gut permeability, and also exert anti-inflammatory effects. [42][43][44][45] Chronic alcohol use changes the composition of the gut microbiome and restoration of the microbial dysbalance is an attractive therapeutic approach. 46,47 An early reduction in Akkermansia has been identified after short-term alcohol feeding in mice and the same defect was seen after chronic alcohol use in mice and humans.…”