SRT1720, a sirtuin 1 activator, attenuates organ injury and inflammation in sepsis

Abstract

Background Sepsis affects 800,000 patients in the US annually with a mortality rate of up to 30%. Recent studies suggest that sepsis-associated metabolic derangements due to hypoxic tissue injury, impaired oxygen utilization, and mitochondrial dysfunction contribute to mortality. Sirtuin 1 (Sirt1) is a crucial modulator of energy metabolism during starvation states and has anti-inflammatory effects. Here, we hypothesized that SRT1720, a Sirt1 activator, could attenuate the severity of sepsis. Materials and Methods Male C57BL/6 mice (20–25g) were subjected to cecal ligation and puncture (CLP) to induce sepsis. SRT1720 (5 or 20 mg/kg BW) or 10% dimethyl sulfoxide (vehicle) in 0.2 ml saline was injected intravenously at 5 h after CLP. Control animals were not subjected to any surgery. Blood and liver samples were harvested at 20 h after CLP for analysis. Results Administration of SRT1720 markedly reduced the serum levels of tissue injury markers (AST, ALT, and LDH) and renal injury markers (BUN and creatinine) in a dose-dependent manner after CLP. Furthermore, the levels of proinflammatory cytokines IL-1β and IL-6 in the serum and liver were significantly inhibited by SRT1720 treatment after CLP. SRT1720 treatment resulted in a significantly decreased mRNA expression of inflammasome components [nucleotide oligomerization domain-like receptor protein 3 (NLRP3), adapter apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC), IL-1β, and IL-18] in the liver, compared to the vehicle group. Conclusions SRT1720 treatment attenuates multi-organ injury in septic mice. SRT1720 treatment also decreases the production of proinflammatory cytokines and reduces inflammasome activation. Thus, pharmacologic stimulation of Sirt1 may present a promising therapeutic strategy for sepsis.

Sirt1 inhibits HG-induced endothelial injury: Role of Mff-based mitochondrial fission and F‑actin homeostasis-mediated cellular migration

“…According to previous studies, SRT1720 was used in the present study to reactivate Sirt1 and upregulate the expression of Sirt1 in diabetic mice to examine the role of Sirt1 in diabetic vasculopathy in vivo (30,60,61). However, SRT1720 has been reported not to be a direct activator of SIRT1 (62).…”

Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice

“…Control mice were intraperitoneally injected with an equal volume of the vehicle. To investigate the effects of SRT1720 (Santa Cruz Biotechnology, Santa Cruz, CA, USA) on cisplatin-induced AKI, mice were intraperitoneally injected with SRT1720 (20 mg/kg) [16,17] for 3 days. The treatment with SRT1720 started 1 h before cisplatin injection.…”

“…Moreover, SRT1720 treatment suppressed ovalbumin-induced airway inflammation [14] and protected against cigarette smoke-induced lung injury [15]. Liver injury after hepatic ischemia-reperfusion [16] and multiorgan injury in sepsis [17] were also attenuated by SRT1720. In this study, we aimed to evaluate whether SRT1720 treatment could ameliorate against cisplatin-induced AKI.…”

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

“…By contrast, enforced PGC-1α expression in human tubular proximal epithelial cells prevented TNF-induced mitochondrial injury, but the in vivo impact on kidney injury was not studied [94]. During sepsis, mechanisms that might restore PGC-1α expression are also activated, such as AMPK and sirtuins [167]. An improved understanding of these compensatory mechanisms may help design therapeutic approaches to preserve PGC-1α levels during s-AKI.…”