Abstract
PPARα is a ligand-dependent transcription factor and its activation is known to play an important role in cell defense through anti-inflammatory and antioxidant effects. MHY3200 (2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2,2-difluoroacetic acid), a novel benzothiazole-derived peroxisome proliferator-activated receptor α (PPARα) agonist, is a synthesized PPARα activator. This study examined the beneficial effects of MHY3200 on age-associated alterations in reactive oxygen species (ROS)/Akt/forkhead box (FoxO) 1 signaling in rat kidneys. Young (7-month-old) and old (22-month-old) rats were treated with MHY3200 (1 mg/kg body weight/day or 3 mg/kg body weight/day) for two weeks. MHY3200 treatment led to a notable decrease in triglyceride and insulin levels in serum from old rats. The elevated kidney ROS level, serum insulin level, and Akt phosphorylation in old rats were reduced following MHY3200 treatment; moreover, FoxO1 phosphorylation increased. MHY3200 treatment led to the increased level of FoxO1 and its target gene, MnSOD. MHY3200 suppressed cyclooxygenase-2 expression by activating PPARα and inhibiting the activation of nuclear factor-κB (NF-κB) in the kidneys of old rats. Our results suggest that MHY3200 ameliorates age-associated renal inflammation by regulating NF-κB and FoxO1 via ROS/Akt signaling.
Highlights
Aging is characterized by physiological changes such as immunosenescence, decreased hormonal secretion and body mass, and lipid accumulation
Total serum cholesterol levels were higher by 1.82-fold in the serum of old rats compared with their young counterparts, but treatment with 1 mg and 3 mg MHY3200 decreased these levels by 1.85-fold and 2.25-fold, respectively (Figure 1B)
Reactive oxygen and nitrogen species associated with defective antioxidant defense capability leads to redox imbalance, which induces the activation of redox-dependent transcription factors that regulate the transcription of diverse proinflammatory mediators [17]
Summary
Aging is characterized by physiological changes such as immunosenescence, decreased hormonal secretion and body mass, and lipid accumulation. PPARs are important transcription factors that participate in a wide range of biological processes, including glucose homeostasis, prostaglandin cascade, proliferation, insulin signaling, lipid and glucose metabolism, tissue remodeling, and cell differentiation. Detailed studies on PPARs have demonstrated their critical roles in both physiological as well as diseased conditions of various tissues [2,3,4]. PPARα is overexpressed in the kidneys and liver, leading to enhanced lipid oxidation and expression of genes encoding antioxidant enzymes such as manganese superoxide dismutase (MnSOD) and catalase [5]. PPARα activation plays a critical role in cellular defense through anti-inflammatory and antioxidant effects [6]
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