FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury

Abstract

Acute kidney injury (AKI) is a serious clinical complication with high morbidity and mortality rates. Despite substantial progress in understanding the mechanism of AKI, no effective therapy is available for treatment or prevention. We previously found that G protein-coupled receptor (GPCR) family member free fatty acid receptor 4 (FFAR4) agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI mice. However, the versatile role of FFAR4 in kidney has not been well characterized. In the study, the expression of FFAR4 was abnormally decreased in tubular epithelial cells (TECs) of cisplatin, cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice, respectively. Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage, whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI mice. Notably, FFAR4, as a key determinant, was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs, which was indicated by senescence-associated β-galactosidase (SA-β-gal) activity, marker protein p53, p21, Lamin B1, phospho-histone H2A.X, phospho-Rb expression, and secretory phenotype IL-6 level. Mechanistically, pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein, where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplatin-induced mice and TECs. These findings highlight the original role of tubular FFAR4 in cellular senescence via AMPK/SirT3 signaling and identify FFAR4 as a potential drug target against AKI.

Structure–Activity Relationship Studies of 2,4,5-Trisubstituted Pyrimidine Derivatives Leading to the Identification of a Novel and Potent Sirtuin 5 Inhibitor against Sepsis-Associated Acute Kidney Injury

“…PCR primers are listed in Table S3. Kidney sections were visualized at 200× and 400× with an AxioCam HRc digital camera (Olympus, Tokyo, Japan) …”

“…One of the most common complications associated with sepsis is acute kidney injury (AKI), − which affects up to 70% of patients admitted to intensive care units. ,− Currently, there is no effective pharmacotherapy for the treatment of sepsis-associated AKI in patients. , Septic AKI is a complex and multifactorial disease, ,, and the development is closely related to renal tubular epithelial cell (RTEC) injury, characterized by oxidative stress, mitochondrial dysfunction, increased release of inflammatory factors, and so on. − As well-known, the kidney ranks second only to the heart in terms of mitochondrial count and oxygen consumption . The proximal tubular epithelial cell (PTEC), a subtype of RTEC, is particularly vulnerable to injury following AKI due to its high metabolic rate. − Therefore, maintaining mitochondrial homeostasis is crucial for proper renal function to treat AKI …”

Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury

“…Compounds JNJ-47965567 (10 mg/kg), 7a (10 mg/kg), 10b (10 mg/kg), 13a (10 mg/kg), and 14a (5, 10, and 20 mg/kg) were injected intraperitoneally twice (30 min before LPS injection and 8 h after LPS injection). CLP mice model was established as previously described . Compound 14a (20 mg/kg) was injected intraperitoneally twice (30 min before CLP operation and 8 h after CLP operation).…”

“…Kidney sections were visualized at 200× and 400× with an AxioCamHRc digital camera (Olympus, Tokyo, Japan). Renal tubular injury was assessed as previously described …”

“…CLP mice model was established as previously described. 59 Compound 14a (20 mg/kg) was injected intraperitoneally twice (30 min before CLP operation and 8 h after CLP operation). In the preliminary toxicity assessment, compound 14a (20 mg/kg) was injected intraperitoneally.…”