Chloride channel accessory 1 integrates chloride channel activity and mTORC1 in aging‐related kidney injury

The mechanism of kidney injury in aging are not well understood. In order to identify hitherto unknown pathways of aging‐related kidney injury, we performed RNA‐Seq on kidney extracts of young and aged mice. Expression of chloride (Cl) channel accessory 1 (CLCA1) mRNA and protein was increased in the kidneys of aged mice. Immunostaining showed a marked increase in CLCLA1 expression in the proximal tubules of the kidney from aged mice. Increased kidney CLCA1 gene expression also correlated with aging in marmosets and in a human cohort. In aging mice, increased renal cortical CLCA1 content was associated with hydrogen sulfide (H₂S) deficiency, which was ameliorated by administering sodium hydrosulfide (NaHS), a source of H₂S. In order to study whether increased CLCA1 expression leads to injury phenotype and the mechanisms involved, stable transfection of proximal tubule epithelial cells overexpressing human CLCA1 (hCLCA1) was performed. Overexpression of hCLCA1 augmented Cl⁻ current via the Ca⁺⁺‐dependent Cl⁻ channel TMEM16A (anoctamin‐1) by patch‐clamp studies. hCLCA1 overexpression also increased the expression of fibronectin, a matrix protein, and induced the senescence‐associated secretory phenotype (SASP). Mechanistic studies underlying these changes showed that hCLCA1 overexpression leads to inhibition of AMPK activity and stimulation of mTORC1 as cellular signaling determinants of injury. Both TMEM16A inhibitor and NaHS reversed these signaling events and prevented changes in fibronectin and SASP. We conclude that CLCA1‐TMEM16A‐Cl⁻ current pathway is a novel mediator of kidney injury in aging that is regulated by endogenous H₂S.     

Effects of dietary macronutrients on the hepatic transcriptome and serum metabolome in mice

Dietary macronutrient composition influences both hepatic function and aging. Previous work suggested that longevity and hepatic gene expression levels were highly responsive to dietary protein, but almost unaffected by other macronutrients. In contrast, we found expression of 4005, 4232, and 4292 genes in the livers of mice were significantly associated with changes in dietary protein (5%–30%), fat (20%–60%), and carbohydrate (10%–75%), respectively. More genes in aging‐related pathways (notably mTOR, IGF‐1, and NF‐kappaB) had significant correlations with dietary fat intake than protein and carbohydrate intake, and the pattern of gene expression changes in relation to dietary fat intake was in the opposite direction to the effect of graded levels of caloric restriction consistent with dietary fat having a negative impact on aging. We found 732, 808, and 995 serum metabolites were significantly correlated with dietary protein (5%–30%), fat (8.3%–80%), and carbohydrate (10%–80%) contents, respectively. Metabolomics pathway analysis revealed sphingosine‐1‐phosphate signaling was the significantly affected pathway by dietary fat content which has also been identified as significant changed metabolic pathway in the previous caloric restriction study. Our results suggest dietary fat has major impact on aging‐related gene and metabolic pathways compared with other macronutrients.     

NEDD4 attenuates phosgene‐induced acute lung injury through the inhibition of Notch1 activation

Phosgene gas leakage can cause life‐threatening acute lung injury (ALI), which is characterized by inflammation, increased vascular permeability, pulmonary oedema and oxidative stress. Although the downregulation of neuronal precursor cell‐expressed developmentally downregulated 4 (NEDD4) is known to be associated with inflammation and oxidative damage, its functions in phosgene‐induced ALI remain unclear. In this study, rats with phosgene‐induced ALI were intravenously injected with NEDD4‐overexpressing lentiviruses to determine the functions of NEDD4 in this inflammatory condition. NEDD4 expression was decreased in the lung parenchyma of phosgene‐exposed control rats, whereas its expression level was high in the NEDD4‐overexpressing rats. Phosgene exposure increased the wet‐to‐dry lung weight ratio, but NEDD4 abrogated this effect. NEDD4 overexpression attenuated phosgene‐induced lung inflammation, lowering the high lung injury score (based on total protein, inflammatory cells and inflammatory factors in bronchoalveolar lavage fluid) and also reduced phosgene‐induced oxidative stress and cell apoptosis. Finally, NEDD4 was found to interact with Notch1, enhancing its ubiquitination and thereby its degradation, thus attenuating the inflammatory responses to ALI. Therefore, we demonstrated that NEDD4 plays a protective role in alleviating phosgene‐induced ALI, suggesting that enhancing the effect of NEDD4 may be a new approach for treating phosgene‐induced ALI.     

Antrodia camphorata polysaccharide improves inflammatory response in liver injury via the ROS/TLR4/NF‐κB signal

Antrodia Camphorata Polysaccharide (ACP) refers to a kind of polysaccharide extracted from the natural porous fungus Antrodia camphorata. This study investigated the mechanism of action of ACP in protecting the liver. The results showed that ACP suppressed the LPS‐induced KC cell activation, reduced the expression of inflammatory factors, increased the SOD level and suppressed ROS expression. In addition, N‐acetylcysteine (NAC) was adopted for pre‐treatment to suppress ROS. The results indicated that NAC synergistically exerted its effect with ACP, suggesting that ACP played its role through suppressing ROS. Further detection revealed that ACP activated the Nrf2 signal. It was discovered in the mouse model that, ACP effectively improved liver injury in mice, decreased ALT and AST levels, and suppressed the expression of inflammatory factors. This study suggests that ACP can exert its effect against oxidative stress via the Nrf2‐ARE signalling, which further improves the production of ROS and the activation of TLR4‐NF‐κB signalling, and protects the liver against liver injury.