DY131 activates ERRγ/TFAM axis to protect against metabolic disorders and acute kidney injury.

Renal tubular injury is considered as the main pathological feature of acute kidney injury (AKI), and mitochondrial dysfunction in renal tubular cells is implicated in the pathogenesis of AKI. The estrogen-related receptor γ (ERRγ) is a member of orphan nuclear receptors which plays a regulatory role in mitochondrial biosynthesis, energy metabolism and many metabolic pathways. Online datasets showed a dominant expression of ERRγ in renal tubules, but the role of ERRγ in AKI is still unknown. In the present study, we investigated the role of ERRγ in the pathogenesis of AKI and the therapeutic efficacy of ERRγ agonist DY131 in several murine models of AKI. ERRγ expression was reduced in kidneys of AKI patients and AKI murine models along with a negative correlation to the severity of AKI. Consistently, silencing ERRγ in vitro enhanced cisplatin-induced tubular cells apoptosis, while ERRγ overexpression in vivo utilizing hydrodynamic-based tail vein plasmid delivery approach alleviated cisplatin-induced AKI. ERRγ agonist DY131 could enhance the transcriptional activity of ERRγ and ameliorate AKI in various murine models. Moreover, DY131 attenuated the mitochondrial dysfunction of renal tubular cells and metabolic disorders of kidneys in AKI, and promoted the expression of the mitochondrial transcriptional factor A (TFAM). Further investigation showed that TFAM could be a target gene of ERRγ and DY131 might ameliorate AKI by enhancing ERRγ-mediated TFAM expression protecting mitochondria. These findings highlighted the protective effect of DY131 on AKI, thus providing a promising therapeutic strategy for AKI.

Diagnostic yield and novel candidate genes by next generation sequencing in 166 children with intrahepatic cholestasis.

BACKGROUND AND AIMS: Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first month of life. METHODS: We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis, and re-analyzed phenotype and whole-exome sequencing (WES) data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. RESULTS: Overall, we identified disease-causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) had metabolic liver diseases, 9 (17%) had syndromic cholestasis, 9 (17%) had progressive familial intrahepatic cholestasis, 3 (6%) had bile acid synthesis defects, 3(6%) had infantile liver failure and 10 (19%) had a phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G > A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By re-analyzing WES data, two patients were newly solved, who had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved WES families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice models. CONCLUSIONS: In a single-center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Our findings suggest that re-evaluating existing WES data from well-phenotyped patients on a regular basis can increase the diagnostic yield for cholestatic liver disease in children.

Roxadustat ameliorates experimental colitis in mice by regulating macrophage polarization through increasing HIF level.

BACKGROUND: Gastro-intestinal (GI) tract inflammation is as a result of inflammatory hypoxia which is also induced by long-standing group of disorders like inflammatory-bowel disease (IBD). Regulation of GI immune homeostasis by macrophage involves hypoxia-inducible factor (HIF). As inhibitor of HIF prolyl hydroxylase, roxadustat (ROX) increases the levels of HIF. METHODS: We induced experimental colitis (EC) model in mice via dextran-sulfate sodium (DSS) to evaluate ROX role in above-mentioned disease. RESULTS: ROX ameliorated EC in mice by blocking colonic length shorten and loss of body weight, thereby reducing scores of disease-activity index (DAI) and histopathology. ROX significantly reduced inflammatory cytokines levels, suppressed M1 and increased M2 macrophage polarization in colonic tissues. Besides, ROX blocked declining hematocrit (HCT) level in blood and increased HIF-1-α and HIF-2-α level in colonic tissues. The inhibitor of HIF-1- α, KC7F2 decreased body weight and colonic length in ROX-treated DSS mice. Meanwhile, DAI scores and histopathology in KC7F2 treated DSS mice were markedly higher than that of treatment with ROX alone. KC7F2 treatments also significantly increased inflammatory cytokines levels, respectively promoted and reduced polarization of M1 and M2 macrophages in colonic tissue from ROX treated mice. Further, KC7F2 treatments inhibited ROX induced HCT level increasing in blood and decreased HIF-1-α and HIF-2-α level in colonic tissue. CONCLUSION: Collectively, we discovered that ROX ameliorated EC in mice by regulating macrophage polarization through promotion of HIF expression. GENERAL SIGNIFICANCE: Taken together, we developed a new application of ROX, which provides new ideas and a scientific basis for IBD treatment.

Targeting mPGES-2 to protect against acute kidney injury via inhibition of ferroptosis dependent on p53.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality but no specific therapy. Microsomal prostaglandin E synthase-2 (mPGES-2) is a PGE2 synthase but can metabolize PGH2 to malondialdehyde by forming a complex with heme. However, the role and mechanism of action of mPGES-2 in AKI remain unclear. To examine the role of mPGES-2, both global and tubule-specific mPGES-2-deficient mice were treated with cisplatin to induce AKI. mPGES-2 knockdown or overexpressing HK-2 cells were exposed to cisplatin to cause acute renal tubular cell injury. The mPGES-2 inhibitor SZ0232 was used to test the translational potential of targeting mPGES-2 in treating AKI. Additionally, mice were subjected to unilateral renal ischemia/reperfusion to further validate the effect of mPGES-2 on AKI. Interestingly, both genetic and pharmacological blockage of mPGES-2 led to decreased renal dysfunction and morphological damage induced by cisplatin and unilateral renal ischemia/reperfusion. Mechanistic exploration indicated that mPGES-2 deficiency inhibited ferroptosis via the heme-dependent regulation of the p53/SLC7A11/GPX4 axis. The present study indicates that mPGES-2 blockage may be a promising therapeutic strategy for AKI.

Mitochondrial antiviral signaling protein: a potential therapeutic target in renal disease.

Mitochondrial antiviral signaling protein (MAVS) is a key innate immune adaptor on the outer mitochondrial membrane that acts as a switch in the immune signal transduction response to viral infections. Some studies have reported that MAVS mediates NF-κB and type I interferon signaling during viral infection and is also required for optimal NLRP3 inflammasome activity. Recent studies have reported that MAVS is involved in various cancers, systemic lupus erythematosus, kidney diseases, and cardiovascular diseases. Herein, we summarize the structure, activation, pathophysiological roles, and MAVS-based therapies for renal diseases. This review provides novel insights into MAVS's role and therapeutic potential in the pathogenesis of renal diseases.

TRAF1 improves cisplatin-induced acute kidney injury via inhibition of inflammation and metabolic disorders.

BACKGROUND: Cisplatin-induced acute kidney injury (AKI) is a severe clinical complication with no satisfactory therapies in the clinic. Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) plays a vital role in both inflammation and metabolism. However, the TRAF1 effect in cisplatin induced AKI needs to be evaluated. METHODS: We observed the role of TRAF1 in eight-week-old male mice and mouse proximal tubular cells both treated with cisplatin by examining the indicators associated with kidney injury, apoptosis, inflammation, and metabolism. RESULTS: TRAF1 expression was decreased in cisplatin-treated mice and mouse proximal tubular cells (mPTCs), suggesting a potential role of TRAF1 in cisplatin-associated kidney injury. TRAF1 overexpression significantly alleviated cisplatin-triggered AKI and renal tubular injury, as demonstrated by reduced serum creatinine (Scr) and urea nitrogen (BUN) levels, as well as the ameliorated histological damage and inhibited upregulation of NGAL and KIM-1. Moreover, the NF-κB activation and inflammatory cytokine production enhanced by cisplatin were significantly blunted by TRAF1. Meanwhile, the increased number of apoptotic cells and enhanced expression of BAX and cleaved Caspase-3 were markedly decreased by TRAF1 overexpression both in vivo and vitro. Additionally, a significant correction of the metabolic disturbance, including perturbations in energy generation and lipid and amino acid metabolism, was observed in the cisplatin-treated mice kidneys. CONCLUSION: TRAF1 overexpression obviously attenuated cisplatin-induced nephrotoxicity, possibly by correcting the impaired metabolism, inhibiting inflammation, and blocking apoptosis in renal tubular cells. GENERAL SIGNIFICANCE: These observations emphasize the novel mechanisms associated to metabolism and inflammation of TRAF1 in cisplatin-induced kidney injury.

TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5.

Renal fibrosis is a common characteristic of various chronic kidney diseases (CKDs) driving the loss of renal function. During this pathological process, persistent injury to renal tubular epithelial cells and activation of fibroblasts chiefly determine the extent of renal fibrosis. In this study, the role of tumor protein 53 regulating kinase (TP53RK) in the pathogenesis of renal fibrosis and its underlying mechanisms is investigated. TP53RK is upregulated in fibrotic human and animal kidneys with a positive correlation to kidney dysfunction and fibrotic markers. Interestingly, specific deletion of TP53RK either in renal tubule or in fibroblasts in mice can mitigate renal fibrosis in CKD models. Mechanistic investigations reveal that TP53RK phosphorylates baculoviral IAP repeat containing 5 (Birc5) and facilitates its nuclear translocation; enhanced Birc5 displays a profibrotic effect possibly via activating PI3K/Akt and MAPK pathways. Moreover, pharmacologically inhibiting TP53RK and Birc5 using fusidic acid (an FDA-approved antibiotic) and YM-155(currently in clinical phase 2 trials) respectively both ameliorate kidney fibrosis. These findings demonstrate that activated TP53RK/Birc5 signaling in renal tubular cells and fibroblasts alters cellular phenotypes and drives CKD progression. A genetic or pharmacological blockade of this axis serves as a potential strategy for treating CKDs.

Role of cuproptosis in understanding diseases.

Cell death is involved in a wide range of physiological and pathological processes. Recently, the term "cuproptosis" was coined to describe a novel type of cell death. This type of cell death, characterized by copper accumulation and proteotoxic stress, is a copper-dependent manner of death. Despite the progress achieved toward a better understanding of cuproptosis, mechanisms and related signaling pathways in physiology and pathology across various diseases remain to be proved. This mini review summarizes current research on cuproptosis and diseases, providing insights into prospective clinical therapies via targeting cuproptosis.

CDC20 inhibition alleviates fibrotic response of renal tubular epithelial cells and fibroblasts by regulating nuclear translocation of ß-catenin.

Fibrosis is a common pathological phenomenon in progressive kidney disease leading to eventual loss of kidney function. Previous studies demonstrated that CDC20 plays a role in cancers by regulating epithelial-mesenchymal transition (EMT) and the infiltration of fibroblasts, suggesting the potential of CDC20 in regulating fibrotic response. However, the role of CDC20 in renal fibrosis is yet unclear. Herein, we reported that renal CDC20 was remarkably upregulated in renal tubular epithelial cells and fibroblasts in chronic kidney disease (CKD) patients, which was in line with a positive correlation with the severity of kidney fibrosis. In mice with unilateral urinary obstruction, CDC20 was also strikingly enhanced, and treatment with Apcin, an inhibitor of CDC20, ameliorated kidney fibrosis. Consistently, the pharmacological inhibition of CDC20 in mouse proximal tubular epithelial cells and rat fibroblasts attenuated TGF-ß1-induced fibrotic responses, while overexpression of CDC20 aggravated such responses. Additional studies revealed that CDC20 induces nuclear translocation of ß-catenin, which in turn initiates and promotes the pathological process of fibrosis in CKD. Thus, enhanced CDC20 in renal tubular cells and fibroblasts promotes renal fibrosis by activating ß-catenin, and CDC20 inhibition may serve as a promising strategy for the prevention and treatment of renal fibrosis.

LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease.

Mitochondria comprise the central metabolic hub of cells and their imbalance plays a pathogenic role in chronic kidney disease (CKD). Here, we studied Lon protease 1 (LONP1), a major mitochondrial protease, as its role in CKD pathogenesis is unclear. LONP1 expression was decreased in human patients and mice with CKD, and tubular-specific Lonp1 overexpression mitigated renal injury and mitochondrial dysfunction in two different models of CKD, but these outcomes were aggravated by Lonp1 deletion. These results were confirmed in renal tubular epithelial cells in vitro. Mechanistically, LONP1 downregulation caused mitochondrial accumulation of the LONP1 substrate, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), which disrupted mitochondrial function and further accelerated CKD progression. Finally, computer-aided virtual screening was performed, which identified a novel LONP1 activator. Pharmacologically, the LONP1 activator attenuated renal fibrosis and mitochondrial dysfunction. Collectively, these results imply that LONP1 is a promising therapeutic target for treating CKD.

A novel 3-phenylglutaric acid derivative (84-B10) alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial oxidative stress-mediated ferroptosis.

Cisplatin is one of the most effective chemotherapy drugs and is widely used for cancer treatment. However, its clinical use is limited by nephrotoxicity. Emerging findings suggested that both ferroptosis and mitochondrial dysfunction mediate cisplatin-induced nephrotoxicity. In the current study, a novel 3-phenylglutaric acid derivative 5-[[2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl]amino]-5-oxo-3-phenylpentanoic acid (referred to as 84-B10) was found to play a protective role in cisplatin-induced acute kidney injury with no tumor promoting effects. A genome-wide transcriptome analysis indicated that the protective effect of 84-B10 might be dependent on antagonizing ferroptosis. In accordance, lipid peroxide accumulation and downregulation of key ferroptosis suppressors were reversed using 84-B10 treatment both in vivo and in vitro. In addition, 84-B10 inhibited cisplatin-induced mitochondrial damage and mitochondrial reactive oxygen species (mtROS) production and restored superoxide dismutases (SODs). Furthermore, 84-B10 showed similar therapeutic effects to MnTBAP (a cell-permeable SOD mimetic) in eliminating mtROS, restoring mitochondrial homeostasis, and inhibiting ferroptosis under cisplatin challenge. Comparable effects of 84-B10 and liproxstatin-1 in ameliorating cisplatin-induced ferroptosis were observed. However, liproxstatin-1 failed to prevent mitochondrial dysfunction. These data indicated that mtROS might act upstream of cisplatin-induced tubular ferroptosis. Taken together, the novel 3-phenylglutaric acid derivative 84-B10 showed therapeutic potential against cisplatin-induced nephrotoxicity possibly by restoring mitochondria homeostasis and inhibiting mtROS-induced ferroptosis, which suggests the potential use of 84-B10 in preventing and treating cisplatin-nephrotoxicity.

Blockade of prostaglandin E2 receptor 4 ameliorates peritoneal dialysis-associated peritoneal fibrosis.

Inflammatory responses in the peritoneum contribute to peritoneal dialysis (PD)-associated peritoneal fibrosis. Results of our previous study showed that increased microsomal prostaglandin E synthase-1-mediated production of prostaglandin E2 (PGE2) contributed to peritoneal fibrosis. However, the role of its downstream receptor in the progression of peritoneal fibrosis has not been established. Here, we examined the role of PGE2 receptor 4 (EP4) in the development of peritoneal fibrosis. EP4 was significantly upregulated in peritoneal tissues of PD patients with ultrafiltration failure, along with the presence of an enhanced inflammatory response. In vitro experiments showed that exposure to high glucose concentrations enhanced EP4 expression in rat peritoneal mesothelial cells (RPMCs). High-glucose-induced expression of inflammatory cytokines (monocyte chemoattractant protein-1, tumour necrosis factor α, and interleukin 1ß) was significantly reduced in RPMCs treated with ONO-AE3-208, an EP4 receptor antagonist. ONO-AE3-208 also significantly decreased the expression of extracellular matrix proteins induced by high glucose concentrations. Furthermore, ONO-AE3-208 blunted activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and phosphorylation of nuclear factor kappa B (NF-κB) (p-p65). To further investigate the functional role of EP4, ONO-AE3-208 was administrated for 4 weeks in a rat model of PD, the results of which showed that ONO-AE3-208 inhibited peritoneal fibrosis and improved peritoneal dysfunction. Additionally, inflammatory cytokines in the peritoneum of PD rats treated with ONO-AE3-208 were downregulated, in line with inhibition of the NLRP3 inflammasome and NF-κB phosphorylation. In conclusion, an EP4 antagonist reduced the development of peritoneal fibrosis, possibly by suppressing NLRP3 inflammasome- and p-p65-mediated inflammatory responses. Our findings suggest that an EP4 antagonist may be therapeutically beneficial for PD-associated peritoneal fibrosis.

Role of USP13 in physiology and diseases.

Ubiquitin specific protease (USP)-13 is a deubiquitinase that removes ubiquitin from substrates to prevent protein degradation by the proteasome. Currently, the roles of USP13 in physiology and pathology have been reported. In physiology, USP13 is highly associated with cell cycle regulation, DNA damage repair, myoblast differentiation, quality control of the endoplasmic reticulum, and autophagy. In pathology, it has been reported that USP13 is important in the pathogenesis of infection, inflammation, idiopathic pulmonary fibrosis (IPF), neurodegenerative diseases, and cancers. This mini-review summarizes the most recent advances in USP13 studies involving its pathophysiological roles in different conditions and provides new insights into the prevention and treatment of relevant diseases, as well as further research on USP13.

Acetaminophen-induced reduction of NIMA-related kinase 7 expression exacerbates acute liver injury.

Background & Aims: Acetaminophen (APAP)-induced acute liver injury (ALI) is a global health issue characterised by an incomplete understanding of its pathogenesis and unsatisfactory therapies. NEK7 plays critical roles in both cell cycle regulation and inflammation. In the present study, we investigated the role and mechanism of NEK7 in APAP-induced ALI. Methods: In mice with NEK7 overexpression (hydrodynamic tail vein injection of NEK7 plasmids), hepatocyte-specific NEK7 knockout (cKO), and inducible NEK7 knockout (iKO), an overdose of APAP was administered to induce ALI. Liver injury was determined by an analysis of serum liver enzymes, pathological changes, inflammatory cytokines, and metabonomic profiles. In vitro, hepatocyte damage was evaluated by an analysis of cell viability, the reactive oxygen species levels, and mitochondrial function in different cell lines. Hepatocyte proliferation and the cell cycle status were determined by Ki-67 staining, EdU staining, and the cyclin levels. Results: NEK7 was markedly downregulated in APAP-induced injured liver and damaged hepatocytes. NEK7 overexpression in the liver significantly alleviated APAP-induced liver injury, as shown by the restored liver function, reduced pathological injury, and decreased inflammation and oxidative stress, which was confirmed in a hepatocyte cell line. Moreover, both NEK7 cKO and iKO mice exhibited exacerbation of APAP-induced ALI. Finally, we determined that cyclin B1-mediated cell cycle progression could mediate the protective effect of NEK7 against APAP-induced ALI. Conclusions: Reduced NEK7 contributes to APAP-induced ALI, possibly by dysregulating cyclins and disturbing cell cycle progression. Lay summary: Acetaminophen-induced acute liver injury is one of the major global health issues, owing to its high incidence, potential severity, and limited therapeutic options. Our current understanding of its pathogenesis is incomplete. Herein, we have shown that reduced NEK7 (a protein with a key role in the cell cycle) exacerbates acetaminophen-induced acute liver injury. Hence, NEK7 could be a possible therapeutic target for the prevention or treatment of this condition.

Immune Regulator Retinoic Acid-Inducible Gene I (RIG-I) in the Pathogenesis of Cardiovascular Disease.

Retinoic acid-inducible gene I (RIG-I) is a cytosolic pattern recognition receptor that contains two CARD domains, an RNA helicase domain, and a C-terminal domain. RIG-I initiates antiviral innate immunity by recognizing exogenous viral RNAs/DNAs. However, some studies have reported that RIG-I activation leads to damage in various organs and tissues in diverse circumstances. Recent studies have shown that RIG-I is involved in cancer, lupus nephritis, immunoglobulin A nephropathy, Crohn's disease, and atherosclerosis. These reports indicate that RIG-I not only participates in antiviral signaling pathways but also exerts an influence on non-viral infectious diseases. RIG-I is widely expressed in immune and non-immune cells including smooth muscle cells, endothelial cells, and cardiomyocytes. A succinct overview of RIG-I and its signaling pathways, with respect to the cardiovascular system, will aid in the development of novel therapeutics for cardiovascular diseases. In this review, we summarize the structure, activation, signaling pathways, and role of RIG-I in cardiovascular diseases.

Isoliquiritin Ameliorates Cisplatin-Induced Renal Proximal Tubular Cell Injury by Antagonizing Apoptosis, Oxidative Stress and Inflammation.

Acute kidney injury (AKI) is a clinical syndrome characterized by morbidity, mortality, and cost. Cis-diamminedichloroplatinum (cisplatin) is a chemotherapeutic agent used to treat solid tumors and hematological malignancies, but its side effects, especially nephrotoxicity, limit its clinical application. Isoliquiritin (ISL), one of the major flavonoid glycoside compounds in licorice, has been reported to have anti-apoptotic, antioxidant, and anti-inflammatory activities. However, the effect and mechanism of ISL on cisplatin-induced renal proximal tubular cell injury remain unknown. In this study, mouse proximal tubular cells (mPTCs) and human proximal tubule epithelial cells (HK2) were administered increasing concentrations of ISL from 7.8125 to 250 µM. Moreover, mPTC and HK2 cells were pretreated with ISL for 6-8 h, followed by stimulation with cisplatin for 24 h. CCK-8 assay was performed to evaluate the cell viability. Apoptosis and reactive oxygen species (ROS) of cells were measured by using flow cytometer and western blotting. Our results showed that ISL had no obvious effect on cell viability. ISL decreased cisplatin-induced cell injury in a dose-dependent manner. ISL also protected against cisplatin-induced cell apoptosis. Meanwhile, the enhanced protein levels of Bax, cleaved caspase-3/caspase-3 ratio, levels of Pp-65/p-65, levels of IL-6, and the production of ROS induced by cisplatin were significantly attenuated by ISL treatment. Moreover, ISL markedly increased the protein levels of Bcl-2 and SOD2, which were reduced by cisplatin stimulation. These results showed that ISL ameliorated cisplatin-induced renal proximal tubular cell injury by antagonizing apoptosis, oxidative stress and inflammation.

Maintaining homeostasis of mitochondria and endoplasmic reticulum with NSC228155 alleviates cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) is a common complication of hospitalization with high mortality. Approximately 30% of patients receiving cisplatin, the first-line chemotherapy treatment, develop AKI. NSC228155 is a novel compound with potential anti-cancer and anti-bacterial effects. Its therapeutic efficacy in other diseases is unclear. In the present study, we investigated the effect of NSC228155 on cisplatin-induced AKI. The mice were consecutively treated with 2.5 mg/kg of NSC228155 for five days and injected with cisplatin (22 mg/kg) via intraperitoneal injection on day three. NSC228155 strikingly improved the renal function by decreasing the serum creatinine by 52.6% in the cisplatin-induced AKI mice model. Pathologically, NSC228155 profoundly alleviated the tubular damage in Periodic Acid-Schiff staining, and significantly reduced the expression of tubular injury markers and apoptosis in the cisplatin-injured mice kidneys. NSC228155 effectively restored the mitochondrial homeostasis by decreasing damaged mitochondria, activating signals for mitochondrial dynamics and recycling, and corrected mitochondrial dysfunction in ATP production and oxidative stress in the cisplatin model. Transcriptomics and metabolomics analysis on the mice renal cortex suggested that NSC228155 profoundly corrected energy metabolism, especially citrate cycle-related pathways, oxidative stress, and endoplasmic reticulum (ER) stress in the cisplatin-induced AKI kidneys. NSC228155 effectively inhibited ER stress induced by cisplatin or tunicamycin in mice kidneys and HK-2 cells. Co-treatment of NSC228155 with 4-phenylbutyrate or MnTBAP showed a similar therapeutic effect in AKI as the inhibitors or NSC228155 alone did, and corrected the mitochondrial dysfunction and ER stress, respectively, indicating the crosstalk between ER and mitochondria played essential roles in the therapeutic effect of NSC228155 in AKI. Together, these results consistently demonstrated that NSC228155 alleviated cisplatin-induced AKI by restoring the homeostasis in mitochondria and ER, suggesting a therapeutic potential and perhaps a novel strategy for drug discovery.

CARMA3: A potential therapeutic target in non-cancer diseases.

Caspase recruitment domain and membrane-associated guanylate kinase-like protein 3 (CARMA3) is a scaffold protein widely expressed in non-hematopoietic cells. It is encoded by the caspase recruitment domain protein 10 (CARD10) gene. CARMA3 can form a CARMA3-BCL10-MALT1 complex by recruiting B cell lymphoma 10 (BCL10) and mucosa-​associated lymphoid tissue lymphoma translocation protein 1 (MALT1), thereby activating nuclear factor-​κB (NF-κB), a key transcription factor that involves in various biological responses. CARMA3 mediates different receptors-dependent signaling pathways, including G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Inappropriate expression and activation of GPCRs and/or RTKs/CARMA3 signaling lead to the pathogenesis of human diseases. Emerging studies have reported that CARMA3 mediates the development of various types of cancers. Moreover, CARMA3 and its partners participate in human non-cancer diseases, including atherogenesis, abdominal aortic aneurysm, asthma, pulmonary fibrosis, liver fibrosis, insulin resistance, inflammatory bowel disease, and psoriasis. Here we provide a review on its structure, regulation, and molecular function, and further highlight recent findings in human non-cancerous diseases, which will provide a novel therapeutic target.

Anti-anemia drug FG4592 retards the AKI-to-CKD transition by improving vascular regeneration and antioxidative capability.

Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia-inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.

Blocking AURKA with MK-5108 attenuates renal fibrosis in chronic kidney disease.

Renal fibrosis, a common feature of chronic kidney disease (CKD), is characterized by excessive deposition of extracellular matrix (ECM) leading to scar formation in the renal parenchyma. Active epithelial-mesenchymal communication (EMC), and the proliferation and activation of fibroblasts are implicated in the causation of renal fibrosis. Aurora-A kinase (AURKA) is a serine/threonine kinase required for the process of mitosis. Dysregulation of AURKA has been demonstrated in the context of various cancers. However, the role of AURKA in CKD-associated fibrosis has not been elucidated. MK-5108, a potent and highly selective AURKA inhibitor, was shown to exhibit anti-cancer activity in recent preclinical and clinical studies. In the present study, we investigated the role of MK-5108 in renal fibrosis employing animal and cell models. In vivo, AURKA was highly expressed in fibrotic kidneys of CKD patients and in mouse kidneys with unilateral ureteral obstruction (UUO). Post treatment with MK-5108 at the 3rd day after UUO remarkably alleviated renal fibrosis, possibly by inhibiting the proliferation and activation of fibroblasts and suppressing the phenotypic transition of renal cells. Moreover, the enhanced inflammatory factors in obstructive kidneys were also repressed. In vitro, MK-5108 treatment inhibited the pro-fibrotic response in renal cells induced by transforming growth factor-ß1. Finally, overexpression of AURKA in renal fibroblasts promoted fibrotic response, while silencing AURKA showed anti-fibrotic effect, further confirming the pro-fibrotic role of AURKA. In this study, inhibition of AURKA by MK-5108 markedly attenuated renal fibrosis. MK-5108 is a potential therapeutic agent for treatment of renal fibrosis in CKD.