Non-alcoholic fatty liver disease (NAFLD) is a global clinical problem. The MD2-TLR4 pathway exacerbates NAFLD progression by promoting inflammation. Long-term exercise is considered to improve NAFLD but the underlying mechanism is still unclear. In this study, we examined the protective effect and molecular mechanism of exercise on high-fat diet (HFD)-induced liver injury. In an HFD-induced NAFLD mouse model, exercise training significantly decreased hepatic steatosis and fibrosis. Interestingly, exercise training blocked the binding of MD2-TLR4 and decreased the downstream inflammatory response. Irisin is a myokine that is highly expressed in response to exercise and exerts anti-inflammatory effects. We found that circulating irisin levels and muscle irisin expression were significantly increased in exercised mice, suggesting that irisin could mediate the effect of exercise on NAFLD. In vitro studies showed that irisin improved lipid metabolism, fibrosis, and inflammation in palmitic acid (PA)-stimulated AML12 cells. Moreover, binding assay results showed that irisin disturbed MD2-TLR4 complex formation by directly binding with MD2 but not TLR4, and interfered with the recognition of stimuli such as PA and lipopolysaccharide with MD2. Our study provides novel evidence that exercise-induced irisin inhibits inflammation via competitive binding with MD2 to improve NAFLD. Thus, irisin could be considered a potential therapy for NAFLD.

Acute kidney injury (AKI), a critical syndrome characterized by a rapid decrease of kidney function, is a global health problem. Src family kinases (SFK) are proto-oncogenes that regulate diverse biological functions including mitochondrial function. Since mitochondrial dysfunction plays an important role in the development of AKI, and since unbalanced SFK activity causes mitochondrial dysfunction, the present study examined the role of SFK in AKI. Lipopolysaccharides (LPS) inhibited mitochondrial biogenesis and upregulated the expression of NGAL, a marker of tubular epithelial cell injury, in mouse proximal tubular epithelial (mProx) cells. These alterations were prevented by PP2, a pan SFK inhibitor. Importantly, PP2 pretreatment significantly ameliorated LPS-induced loss of kidney function and injury including inflammation and oxidative stress. The attenuation of LPS-induced AKI by PP2 was accompanied by the maintenance of mitochondrial biogenesis. LPS upregulated SFK, especially Fyn and Src, in mouse kidney as well as in mProx cells. These data suggest that Fyn and Src kinases are involved in the pathogenesis of LPS-induced AKI, and that inhibition of Fyn and Src kinases may have a potential therapeutic effect, possibly via improving mitochondrial biogenesis.

Acute kidney injury (AKI) most commonly appears in critically ill patients in hospitals. AKI is characterized as a quick deterioration of kidney function and has recently been identified to be tightly interlinked with chronic kidney diseases. The emerging major mediators of AKI include oxidative stress and endoplasmic reticulum (ER) stress. Carbon monoxide (CO) attenuates oxidative stress and ER stress in various cells, while Fyn, a member of the Src kinase family, is activated by oxidative stress and contributes to ER stress in skeletal muscle. Considering these, the objective of the current research was to determine (i) the involvement of Fyn in ER stress‐mediated AKI and (ii) the effect of CO‐releasing molecule‐2 (CORM2) on reactive oxygen species‐ (ROS‐) Fyn‐ER stress‐mediated AKI. Pretreatment with CORM2 (30 mg/kg) efficiently inhibited LPS (30 mg/kg)‐induced oxidative stress, inflammation, and cellular apoptosis during AKI in C57BL/6J mice. Also, CORM2 efficiently suppressed the activation of Fyn and ER stress in AKI mice. Consistently, pretreatment with CORM2 inhibited oxidative stress, Fyn activation, ER stress, inflammation, and apoptosis in LPS‐ or H₂O₂‐stimulated proximal epithelial tubular cells. Fyn inhibition using siRNA or an inhibitor (PP2) significantly attenuated ER stress responses in the cells. These data suggest that CORM2 may become a potential treatment option against ROS‐Fyn‐ER stress‐mediated AKI.

Diabetic kidney disease (DKD) is now a pandemic worldwide, and novel therapeutic options are urgently required. Adenosine, an adenosine triphosphate metabolite, plays a role in kidney homeostasis through interacting with four types of adenosine receptors (ARs): A1AR, A2AAR, A2BAR, and A3AR. Increasing evidence highlights the role of adenosine and ARs in the development and progression of DKD: 1) increased adenosine in the plasma and urine of diabetics with kidney injury, 2) increased expression of each of the ARs in diabetic kidneys, 3) the protective effect of coffee, a commonly ingested nonselective AR antagonist, on DKD, and 4) the protective effect of AR modulators in experimental DKD models. We propose AR modulators as a new therapeutic option to treat DKD. Detailed mechanistic studies on the pharmacology of AR modulators will help us to develop effective first-in-class AR modulators against DKD.

Kidney fibrosis is the final outcome of chronic kidney disease (CKD). Adenosine plays a significant role in protection against cellular damage by activating four subtypes of adenosine receptors (ARs), A₁AR, A_2AAR, A_2BAR, and A₃AR. A_2AAR agonists protect against inflammation, and A₃AR antagonists effectively inhibit the formation of fibrosis. Here, we showed for the first time that LJ-4459, a newly synthesized dual-acting ligand that is an A_2AAR agonist and an A₃AR antagonist, prevents the progression of tubulointerstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed on 6-week-old male C57BL/6 mice. LJ-4459 (1 and 10 mg/kg) was orally administered for 7 days, started at 1 day before UUO surgery. Pretreatment with LJ-4459 improved kidney morphology and prevented the progression of tubular injury as shown by decreases in urinary kidney injury molecular-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion. Obstruction-induced tubulointerstitial fibrosis was attenuated by LJ-4459, as shown by a decrease in fibrotic protein expression in the kidney. LJ-4459 also inhibited inflammation and oxidative stress in the obstructed kidney, with reduced macrophage infiltration, reduced levels of pro-inflammatory cytokines, as well as reduced levels of reactive oxygen species (ROS). These data demonstrate that LJ-4459 has potential as a therapeutic agent against the progression of tubulointerstitial fibrosis.

Lipid metabolism, particularly fatty acid oxidation dysfunction, is a major driver of renal fibrosis. However, the detailed regulatory mechanisms underlying this process remain unclear. Here we demonstrated that acyl-CoA thioesterase 12 (Acot12), an enzyme involved in the hydrolysis of acyl-CoA thioesters into free fatty acids and CoA, is a key regulator of lipid metabolism in fibrotic kidneys. A significantly decreased level of ACOT12 was observed in kidney samples from human patients with chronic kidney disease as well as in samples from mice with kidney injuries. Acot12 deficiency induces lipid accumulation and fibrosis in mice subjected to unilateral ureteral obstruction (UUO). Fenofibrate administration does not reduce renal fibrosis in Acot12 ^−/− mice with UUO. Moreover, the restoration of peroxisome proliferator-activated receptor α (PPARα) in Acot12 ^−/− Pparα ^−/− kidneys with UUO exacerbated lipid accumulation and renal fibrosis, whereas the restoration of Acot12 in Acot12 ^−/− Pparα ^−/− kidneys with UUO significantly reduced lipid accumulation and renal fibrosis, suggesting that, mechanistically, Acot12 deficiency exacerbates renal fibrosis independently of PPAR α . In Acot12 ^−/− kidneys with UUO, a reduction in the selective autophagic degradation of peroxisomes and pexophagy with a decreased level of ACBD5 was observed. In conclusion, our study demonstrates the functional role and mechanistic details of Acot12 in the progression of renal fibrosis, provides a preclinical rationale for regulating Acot12 expression and presents a novel means of preventing renal fibrosis.