STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury.

Recently, innate immunity and inflammation were recognized as the key factors for acute kidney injury (AKI) caused by sepsis, which is closely related to high mortality. Stimulator of interferon genes (STING) has emerged as a critical component of innate immune and inflammatory responses. However, the role of STING in the pathogenesis of septic AKI remains unclear. This study demonstrated that the STING was significantly activated in tubular cells induced by lipopolysaccharide (LPS) in vivo and in vitro. Tubule-specific STING knockout attenuated LPS-induced renal dysfunction and pathological changes. Mechanistically, the STING pathway promotes NOD-like receptor protein 3 (NLRP3) activation. STING triggers endoplasmic reticulum (ER) stress to induce mitochondrial reactive oxygen species (mtROS) overproduction, enhancing thioredoxin-interacting protein activation and association with NLRP3. Eventually, the NLRP3 inflammasome leads to tubular cell inflammation and pyroptosis. This study revealed the STING-regulated network and further identified the STING/ER stress/mtROS/NLRP3 inflammasome axis as an emerging pathway contributing to tubular damage in LPS-induced AKI. Hence, targeting STING may be a promising therapeutic strategy for preventing septic AKI.

ALCAT1-mediated abnormal cardiolipin remodelling promotes mitochondrial injury in podocytes in diabetic kidney disease.

BACKGROUND: Cardiolipin (CL) plays a critical role in maintaining mitochondrial membrane integrity and overall mitochondrial homeostasis. Recent studies have suggested that mitochondrial damage resulting from abnormal cardiolipin remodelling is associated with the pathogenesis of diabetic kidney disease (DKD). Acyl-coenzyme A:lyso-cardiolipin acyltransferase-1 (ALCAT1) was confirmed to be involved in the progression of Parkinson's disease, diet-induced obesity and other ageing-related diseases by regulating pathological cardiolipin remodelling. Thus, the purpose of this investigation was to determine the role of ALCAT1-mediated CL remodelling in DKD and to explore the potential underlying mechanism. METHODS: In vivo study, the mitochondrial structure was examined by transmission electron microscopy (TEM). The colocalization of ALCAT1 and synaptopodin was evaluated by double immunolabelling. Western blotting (WB) was performed to assess ALCAT1 expression in glomeruli. Lipidomics analysis was conducted to evaluate the composition of reconstructed cardiolipins. In vitro study, the lipidomics, TEM and WB analyses were similar to those in vivo. Mitochondrial function was evaluated by measuring the mitochondrial membrane potential (MMP) and the production of ATP and ROS. RESULTS: Here, we showed that increased oxidized cardiolipin (ox-CL) and significant mitochondrial damage were accompanied by increased ALCAT1 expression in the glomeruli of patients with DKD. Similar results were found in db/db mouse kidneys and in cultured podocytes stimulated with high glucose (HG). ALCAT1 deficiency effectively prevented HG-induced ox-CL production and mitochondrial damage in podocytes. In contrast, ALCAT1 upregulation enhanced ox-CL levels and podocyte mitochondrial dysfunction. Moreover, treatment with the cardiolipin antioxidant SS-31 markedly inhibited mitochondrial dysfunction and cell injury, and SS-31 treatment partly reversed the damage mediated by ALCAT1 overexpression. We further found that ALCAT1 could mediate the key regulators of mitochondrial dynamics and mitophagy through the AMPK pathway. CONCLUSIONS: Collectively, our studies demonstrated that ALCAT1-mediated cardiolipin remodelling played a crucial role in DKD, which might provide new insights for DKD treatment. Video Abstract.

CLMP is a tumor suppressor that determines all-trans retinoic acid response in colorectal cancer.

CAR-like membrane protein (CLMP) is a tight junction-associated protein whose mutation is associated with congenital short bowel syndrome (CSBS), but its functions in colorectal cancer (CRC) remain unknown. Here, we demonstrate that CLMP is rarely mutated but significantly decreased in CRC patients, and its deficiency accelerates CRC tumorigenesis, growth, and resistance to all-trans retinoic acid (ATRA). Mechanistically, CLMP recruits ß-catenin to cell membrane, independent of cadherin proteins. CLMP-mediated ß-catenin translocation inactivates Wnt(Wingless and INT-1)/ß-catenin signaling, thereby suppressing CRC tumorigenesis and growth in ApcMin/+, azoxymethane/dextran sodium sulfate (AOM/DSS), and orthotopic CRC mouse models. As a direct target of Wnt/ß-catenin, cytochrome P450 hydroxylase A1 (CYP26A1)-an enzyme that degrades ATRA to a less bioactive retinoid-is upregulated by CLMP deficiency, resulting in ATRA-resistant CRC that can be reversed by administering CYP26A1 inhibitor. Collectively, our data identify the anti-CRC role of CLMP and suggest that CYP26A1 inhibitor enable to boost ATRA's therapeutic efficiency.

Nosocomial Outbreak of Colistin-Resistant, Carbapenemase-Producing Klebsiella Pneumoniae ST11 in a Medical Intensive Care Unit.

OBJECTIVES: Klebsiella pneumoniae is an important opportunistic Gram-negative pathogen. This study describes an outbreak due to colistin resistant and Carbapenemase-producing Klebsiella pneumoniae (ColR-CRKP) in a tertiary hospital related to six patients successively admitted to the department of medical intensive care unit (MICU) between March 11 and April 29, 2021. METHODS: Phenotypic characterization was conducted on 16 ColR-CRKP strains obtained from six infected patients and five ColR-CRKP strains isolated from 48 environmental samples, followed by whole genome sequencing (WGS) and PCR analysis. RESULTS: All ColR-CRKP strains showed resistance to commonly used antibiotics. WGS revealed a variety of resistance genes such as blaKPC-2, blaCTX-M-65 and blaTEM-4 present in all strains, which is consistent with their antimicrobial resistance profile. All isolates were identified as the high-risk sequence type 11 (ST11) clonal lineage by multilocus sequencing typing (MLST) and subsequently clustered into a single clonal type by core genome MLST (cgMLST). IS5-like element ISKpn26 family transposase insertion mutations at positions 74 nucleotides in the mgrB gene were the main cause of colistin resistance in these ColR-CRKP. The variations of genes were verified by PCR. SCOTTI analysis demonstrated the transmission pathway of the ColR-CRKP between the patients. CONCLUSION: Our study highlights the importance of coordinated efforts between clinical microbiologists and infection control teams to implement aggressive surveillance cultures and proper bacterial genotyping to diagnose nosocomial infections and take control measures. Routine surveillance and the use of advanced sequencing technologies should be implemented to enhance nosocomial infection control and prevention measures.

PFKFB3 downregulation aggravates Angiotensin II-induced podocyte detachment.

Podocytes play a critical role in maintaining normal glomerular filtration, and podocyte loss from the glomerular basement membrane (GBM) initiates and worsens chronic kidney disease (CKD). However, the exact mechanism underlying podocyte loss remains unclear. Fructose-2,6-biphosphatase 3 (PFKFB3) is a bifunctional enzyme that plays crucial roles in glycolysis, cell proliferation, cell survival, and cell adhesion. This study aimed to determine the role of PFKFB3 in angiotensin II (Ang II) kidney damage. We found that mice infused with Ang II developed glomerular podocyte detachment and impaired renal function accompanied by decreased PFKFB3 expression in vivo and in vitro. Inhibition of PFKFB3 with the PFKFB3 inhibitor 3PO further aggravated podocyte loss induced by Ang II. In contrast, activating PFKFB3 with the PFKFB3 agonist meclizine alleviated the podocyte loss induced by Ang II. Mechanistically, PFKFB3 knockdown likely aggravate Ang II-induced podocyte loss by suppressing talin1 phosphorylation and integrin beta1 subunit (ITGB1) activity. Conversely, PFKFB3 overexpression protected against Ang II-induced podocyte loss. These findings suggest that Ang II leads to a decrease in podocyte adhesion by suppressing PFKFB3 expression, and indicates a potential therapeutic target for podocyte injury in CKD.

STING deletion alleviates podocyte injury through suppressing inflammation by targeting NLRP3 in diabetic kidney disease.

An increasing number of studies have shown that immune inflammatory response plays a vital role in diabetic kidney disease (DKD). Nod-like receptor protein 3 (NLRP3) inflammasome-dependent inflammatory response is a key mechanism in the initiation and development of DKD. The stimulator of interferon genes (STING) is an adaptor protein that can drive noninfectious inflammation and pyroptosis. However, the mechanism of STING regulating immune inflammation and the interaction with NLRP3-dependent pyroptosis in high glucose state still remains unclear. This study evaluated the potential role of STING in high glucose (HG)-induced podocyte inflammation response. STING expression was significantly increased in db/db mice, STZ-treated diabetic mice, and HG-treated podocytes. Podocyte-specific deletion of STING alleviated podocyte injury, renal dysfunction, and inflammation in STZ-induced diabetic mice. STING inhibitor (H151) administration ameliorated inflammation and improved renal function in db/db mice. STING deletion in podocytes attenuated the activation of the NLRP3 inflammasome and podocyte pyroptosis in STZ-induced diabetic mice. In vitro, modulated STING expression by STING siRNA alleviated pyroptosis and NLRP3 inflammasome activation in HG-treated podocytes. NLRP3 over-expression offset the beneficial effects of STING deletion. These results indicate that STING deletion suppresses podocyte inflammation response through suppressing NLRP3 inflammasome activation and provide evidence that STING may be a potential target for podocyte injury in DKD.

LRH-1 activation alleviates diabetes-induced podocyte injury by promoting GLS2-mediated glutaminolysis.

Alteration of metabolic phenotype in podocytes directly contributes to the development of albuminuria and renal injury in conditions of diabetic kidney disease (DKD). This study aimed to identify and evaluate liver receptor homologue-1 (LRH-1) as a possible therapeutic target that alleviates glutamine (Gln) metabolism disorders and mitigates podocyte injury in DKD. Metabolomic and transcriptomic analyses were performed to characterize amino acid metabolism changes in the glomeruli of diabetic mice. Next, Western blotting, immunohistochemistry assays, and immunofluorescence staining were used to detect the expression of different genes in vitro and in vivo. Furthermore, Gln and glutamate (Glu) content as well as ATP generation were examined. A decrease in LRH-1 and glutaminase 2 (GLS2) expression was detected in diabetic podocytes. Conversely, the administration of LRH-1 agonist (DLPC) upregulated the expression of GLS2 and promoted glutaminolysis, with an improvement in mitochondrial dysfunction and less apoptosis in podocytes compared to those in vehicle-treated db/db mice. Our study indicates the essential role of LRH-1 in governing the Gln metabolism of podocytes, targeting LRH-1 could restore podocytes from diabetes-induced disturbed glutaminolysis in mitochondria.

Vitamin D receptor (VDR) mediates the quiescence of activated hepatic stellate cells (aHSCs) by regulating M2 macrophage exosomal smooth muscle cell-associated protein 5 (SMAP-5). / ç»´ç”Ÿç´ D受体（VDR）通过调节M2巨噬细胞外泌体SMAP-5介导肝星状细胞的静息.

An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism. Hepatic fibrosis is characterized by activated hepatic stellate cells (aHSCs) with an excessive production of extracellular matrix. Although promoted activation of HSCs by M2 macrophages has been demonstrated, the molecular mechanism involved remains ambiguous. Herein, we propose that the vitamin D receptor (VDR) involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes. We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation. The exosomes derived from M2 macrophages can promote HSC activation, while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes. Smooth muscle cell-associated protein 5 (SMAP-5) was found to be the key effector protein in promoting HSC activation by regulating autophagy flux. Building on these results, we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect. In this study, we aim to elucidate the association between VDR and macrophages in HSC activation. The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis, and provide potential therapeutic targets for its treatment.

Reduction of anaerobic glycolysis contributes to angiotensin II-induced podocyte injury with foot process effacement.

Activation of the renin-angiotensin system is associated with podocyte injury and has been well demonstrated as a pivotal factor in the progression of chronic kidney disease. Podocyte energy metabolism is crucial for maintaining their physiological functions. However, whether renin-angiotensin system activation promotes chronic kidney disease progression by disturbing the energy metabolism of podocytes has not been elucidated. Angiotensin II, the main active molecule of the renin-angiotensin system, plays a crucial role in chronic kidney disease initiation and progression, but its impact on podocyte metabolism remains unclear. Here, we demonstrate a rapid decrease in the expression of pyruvate kinase M2, a key glycolytic enzyme, and reduced glycolytic flux in podocytes exposed to angiotensin II in vivo and in vitro. Podocyte-specific deletion of pyruvate kinase M2 in mice aggravated angiotensin II-induced glomerular and podocyte injury with foot process effacement and proteinuria. The inhibition of glycolysis was accompanied by adenosine triphosphate deficiency, cytoskeletal remodeling and podocyte apoptosis. Mechanistically, we found that angiotensin II-induced glycolysis impairment contributed to an insufficient energy supply to the foot process, leading to podocyte injury. Additionally, pyruvate kinase M2 expression was found to be reduced in podocytes from kidney biopsies of patients with hypertensive nephropathy and diabetic kidney disease. Thus, our findings suggest that glycolysis activation is a potential therapeutic strategy for podocyte injury.

Investigating the heat tolerance and production performance in local chicken breed having normal and dwarf size.

Heat stress significantly impairs the growth performance of broilers, which causes serious losses to the poultry industry every year. Thus, understanding the performance of indigenous chicken breeds under such environment is crucial to address heat stress problem. The purpose of this study was to investigate the effects of heat stress (HS) on production performance, tissue histology, heat shock response (HSP70, HSP90), and muscle growth-related genes (GHR, IGF-1, and IGF-1R) of Normal yellow chicken (NYC) and Dwarf yellow chicken (DYC). Seventy-two female birds from each strain were raised under normal environmental conditions up to 84 days, with birds from each strain being divided into two groups (HS and control). In the HS group, birds were subjected to high temperature at 35 ± 1 °C for 8 h daily and lasted for a week, while in the control group, birds were raised at 28 ± 1 °C. At 91 days old, bird's liver, hypothalamus, and breast muscle tissues were collected to evaluate the gene expression, histological changes, and the production performance. The Feed intake, weight gain ratio, total protein intake and protein efficiency ratio showed a significant reduction in the treatments (P < 0.01) and treatment × strain interaction (P < 0.05) with breast muscle rate significantly reducing among the treatments (P < 0.01) after 7 days of HS. Correspondingly, total abdominal fat showed significant change among treatment and strain (P < 0.01, P < 0.05), respectively. Besides, HS markedly upregulated the mRNA expression of HSP70 and HSP90 in the pectoralis major of both chicken strains, but no significant increase (P < 0.05) was found in mRNA expression of HSP90 in liver and hypothalamus tissues of both chicken strains. Moreover, HS significantly upregulated (P < 0.05) the expression of lipogenic genes (FASN, ACC) in liver tissues of NYC, while mRNA expression of these genes showed no variation in DYC. Similarly, HS downregulated the mRNA expression of muscle growth-related genes (GHR, IGF-1, and IGF-1R). Consequently, the histopathological analysis showed that histological changes were accompanied by inflammatory cell infiltration in liver tissues of both chicken strains; however, histopathological changes were more severe in NYC than dwarf chicken strain. Conclusively, this study depicted that the production performance and growth rate varied significantly between treatment and control group of NYC. However, heat treatment in DYC has not shown significant damaging consequences as compared to the control group that signifies the vital role of the dwarf trait in thermal tolerance.

Mitochondria-Targeted Antioxidant Mitoquinone Maintains Mitochondrial Homeostasis through the Sirt3-Dependent Pathway to Mitigate Oxidative Damage Caused by Renal Ischemia/Reperfusion.

Mitochondrial dysfunction is a critical factor contributing to oxidative stress and apoptosis in ischemia-reperfusion (I/R) diseases. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant whose potent anti-I/R injury capacity has been demonstrated in organs such as the heart and the intestine. In the present study, we explored the role of MitoQ in maintaining mitochondrial homeostasis and attenuating oxidative damage in renal I/R injury. We discovered that the decreased renal function and pathological damage caused by renal I/R injury were significantly ameliorated by MitoQ. MitoQ markedly reversed mitochondrial damage after I/R injury and inhibited renal reactive oxygen species production. In vitro, hypoxia/reoxygenation resulted in increased mitochondrial fission and decreased mitochondrial fusion in human renal tubular epithelial cells (HK-2), which were partially prevented by MitoQ. MitoQ treatment inhibited oxidative stress and reduced apoptosis in HK-2 cells by restoring mitochondrial membrane potential, promoting ATP production, and facilitating mitochondrial fusion. Deeply, renal I/R injury led to a decreased expression of sirtuin-3 (Sirt3), which was recovered by MitoQ. Moreover, the inhibition of Sirt3 partially eliminated the protective effect of MitoQ on mitochondria and increased oxidative damage. Overall, our data demonstrate a mitochondrial protective effect of MitoQ, which raises the possibility of MitoQ as a novel therapy for renal I/R.

Angiotensin II induces podocyte metabolic reprogramming from glycolysis to glycerol-3-phosphate biosynthesis.

Recent studies have reported that Angiotensin II (Ang II) contributes to podocyte injury by interfering with metabolism. Glycolysis is essential for podocytes and glycolysis abnormality is associated with glomerular injury in chronic kidney disease (CKD). Glycerol-3-phosphate (G-3-P) biosynthesis is a shunt pathway of glycolysis, in which cytosolic glycerol-3-phosphate dehydrogenase 1 (GPD1) catalyzes dihydroxyacetone phosphate (DHAP) to generate G-3-P in the presence of the NADH. G-3-P is not only a substrate in glycerophospholipids and glyceride synthesis but also can be oxidated by mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) to regenerate DHAP in mitochondria. Since G-3-P biosynthesis links to glycolysis, mitochondrial metabolism and lipid synthesis, we speculate G-3-P biosynthesis abnormality is probably involved in podocyte injury. In this study, we demonstrated that Ang II upregulated GPD1 expression and increased G-3-P and glycerophospholipid syntheses in podocytes. GPD1 knockdown protected podocytes from Ang II-induced lipid accumulation and mitochondrial dysfunction. GPD1 overexpression exacerbated Ang II-induced podocyte injury. In addition, we proved that lipid accumulation and mitochondrial dysfunction were correlated with G-3-P content in podocytes. These results suggest that Ang II upregulates GPD1 and promotes G-3-P biosynthesis in podocytes, which promote lipid accumulation and mitochondrial dysfunction in podocytes.

Compromised glycolysis contributes to foot process fusion of podocytes in diabetic kidney disease: Role of ornithine catabolism.

INTRODUCTION: Compromised glycolysis in podocytes contributes to the initiation of diabetic kidney disease (DKD). Podocyte injury is characterized by cytoskeletal remodeling and foot process fusion. Compromised glycolysis in diabetes likely leads to switch of energy supply in podocyte. However, the underlying mechanism by which disturbed energy supply in podocytes affects the cytoskeletal structure of podocytes remains unclear. METHODS: Metabolomic and transcriptomic analyses were performed on the glomeruli of db/db mice to examine the catabolism of glucose, fatty, and amino acids. Ornithine catabolism was targeted in db/db and podocyte-specific pyruvate kinase M2 knockout (PKM2-podoKO) mice. In vitro, expression of ornithine decarboxylase (ODC1) was modulated to investigate the effect of ornithine catabolism on mammalian target of rapamycin (mTOR) signaling and cytoskeletal remodeling in cultured podocytes. RESULTS: Multi-omic analyses of the glomeruli revealed that ornithine metabolism was enhanced in db/db mice compared with that in db/m mice under compromised glycolytic conditions. Additionally, ornithine catabolism was exaggerated in podocytes of diabetic PKM2-podoKO mice compared with that in diabetic PKM2flox/flox mice. In vivo, difluoromethylornithine (DFMO, inhibitor of ODC1) administration reduced urinary albumin excretion and alleviated podocyte foot process fusion in db/db mice. In vitro, 2-deoxy-d-glucose (2-DG) exposure induced mTOR signaling activation and cytoskeletal remodeling in podocytes, which was alleviated by ODC1-knockdown. Mechanistically, a small GTPase Ras homolog enriched in the brain (Rheb), a sensor of mTOR signaling, was activated by exposure to putrescine, a metabolic product of ornithine catabolism. CONCLUSION: These findings demonstrate that compromised glycolysis in podocytes under diabetic conditions enhances ornithine catabolism. The metabolites of ornithine catabolism contribute to mTOR signaling activation via Rheb and cytoskeletal remodeling in podocytes in DKD.

Sirt6 deficiency contributes to mitochondrial fission and oxidative damage in podocytes via ROCK1-Drp1 signalling pathway.

OBJECTIVES: Increasing evidence suggests that mitochondrial dysfunction is the key driver of angiotensin II (Ang II)-induced kidney injury. This study was designed to investigate whether Sirtuin 6 (Sirt6) could affect Ang II-induced mitochondrial damage and the potential mechanisms. MATERIALS AND METHODS: Podocyte-specific Sirt6 knockout mice were infused with Ang II and cultured podocytes were stimulated with Ang II to evaluate the effects of Sirt6 on mitochondrial structure and function in podocytes. Immunofluorescence staining was used to detect protein expression and mitochondrial morphology in vitro. Electron microscopy was used to assess mitochondrial morphology in mice. Western blotting was used to quantify protein expression. RESULTS: Mitochondrial fission and decreased Sirt6 expression were observed in podocytes from Ang II-infused mice. In Sirt6-deficient mice, Ang II infusion induced increased apoptosis and mitochondrial fragmentation in podocytes than that in Ang II-infused wild-type mice. In cultured human podocytes, Sirt6 knockdown exacerbated Ang II-induced mitochondrial fission, whereas Sirt6 overexpression ameliorated the Ang II-induced changes in the balance between mitochondrial fusion and fission. Functional studies revealed that Sirt6 deficiency exacerbated mitochondrial fission by promoting dynamin-related protein 1 (Drp1) phosphorylation. Furthermore, Sirt6 mediated Drp1 phosphorylation by promoting Rho-associated coiled coil-containing protein kinase 1 (ROCK1) expression. CONCLUSION: Our study has identified Sirt6 as a vital factor that protects against Ang II-induced mitochondrial fission and apoptosis in podocytes via the ROCK1-Drp1 signalling pathway.

AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease.

Podocyte injury is involved in the onset and progression of diabetic kidney disease (DKD) and is associated with mitochondrial abnormalities. Defective mitochondrial DNA (mtDNA) replication results in mitochondrial dysfunction. However, whether podocyte mtDNA replication is impaired in DKD is still unclear. A-kinase anchoring protein 1 (AKAP1) is localized in the outer mitochondrial membrane (OMM) and acts as a regulator and conductor of mitochondrial signals. Herein, we investigated the role of AKAP1 in high glucose-induced mtDNA replication. Decreased mtDNA replication and mitochondrial dysfunction occurred in podocytes of DKD. AKAP1 expression was up-regulated, and protein kinase C (PKC) signaling was activated under hyperglycemic conditions. AKAP1 recruited PKC and mediated La-related protein 1 (Larp1) phosphorylation, which reduced the expression of mitochondrial transcription factor A (TFAM), a key factor in mtDNA replication. In addition, mtDNA replication, mitochondrial function and podocyte injury were rescued by knocking down AKAP1 expression and the PKC inhibitor enzastaurin. In contrast, AKAP1 overexpression worsened the impairment of mtDNA replication and podocyte injury. In conclusion, our study revealed that AKAP1 phosphorylates Larp1 via PKC signaling activation to decrease mtDNA replication, which accelerates mitochondrial dysfunction and podocyte injury in DKD.

Alteration in Rab11-mediated endocytic trafficking of LDL receptor contributes to angiotensin II-induced cholesterol accumulation and injury in podocytes.

OBJECTIVES: Exposure of podocytes to angiotensin II (Ang II) enhances the abundance of the cell surface glycoprotein, low-density lipoprotein receptor (LDLR) and promotes significant changes in the cellular cholesterol content. Recent investigation provides evidence that the small GTPase Rab11 is involved in the regulation of LDLR, but the exact mechanisms remain unknown. In this study, the role of Rab11 in post-transcriptional regulation of LDLR was evaluated to investigate potential mechanisms of podocyte cholesterol dysregulation in chronic kidney disease. MATERIALS AND METHODS: Cholesterol content, LDLR and Rab11 expression were assessed in podocytes from Ang II-infused mice. In vitro, the intracellular localization of LDLR was detected under different conditions. Rab11 expression was modulated and we then explored the effect of anti-lipid cytotoxicity by detecting LDLR expression and trafficking, cholesterol content and apoptosis in podocytes. RESULTS: Cholesterol accumulation, upregulated expression of LDLR and Rab11 were discovered in podocytes from Ang II-infused mice. Ang II enhanced the co-precipitation of LDLR with Rab11 and accelerated the endocytic recycling of LDLR to the plasma membrane. Additionally, silencing Rab11 promoted lysosomal degradation of LDLR and alleviated Ang II-induced cholesterol accumulation and apoptosis in podocytes. Conversely, overexpression of Rab11 or inhibition of lysosomal degradation up-regulated the abundance of LDLR and aggravated podocyte cholesterol deposition. CONCLUSIONS: Rab11 triggers the endocytic trafficking and recycling of LDLR; overactivation of this pathway contributes to Ang II-induced podocyte cholesterol accumulation and injury.

Transition of acute kidney injury to chronic kidney disease: role of metabolic reprogramming.

Acute kidney injury (AKI) is a global public health concern associated with high morbidity and mortality. Although advances in medical management have improved the in-hospital mortality of severe AKI patients, the renal prognosis for AKI patients in the later period is not encouraging. Recent epidemiological investigations have indicated that AKI significantly increases the risk for the development of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the future, further contributing to the economic burden on health care systems. The transition of AKI to CKD is complex and often involves multiple mechanisms. Recent studies have suggested that renal tubular epithelial cells (TECs) are more prone to metabolic reprogramming during AKI, in which the metabolic process in the TECs shifts from fatty acid ß-oxidation (FAO) to glycolysis due to hypoxia, mitochondrial dysfunction, and disordered nutrient-sensing pathways. This change is a double-edged role. On the one hand, enhanced glycolysis acts as a compensation pathway for ATP production; on the other hand, long-term shut down of FAO and enhanced glycolysis lead to inflammation, lipid accumulation, and fibrosis, contributing to the transition of AKI to CKD. This review discusses developments and therapies focused on the metabolic reprogramming of TECs during AKI, and the emerging questions in this evolving field.

Roles of SIRT6 in kidney disease: a novel therapeutic target.

SIRT6 is an NAD+ dependent deacetylase that belongs to the mammalian sirtuin family. SIRT6 is mainly located in the nucleus and regulates chromatin remodeling, genome stability, and gene transcription. SIRT6 extensively participates in various physiological activities such as DNA repair, energy metabolism, oxidative stress, inflammation, and fibrosis. In recent years, the role of epigenetics such as acetylation modification in renal disease has gradually received widespread attention. SIRT6 reduces oxidative stress, inflammation, and renal fibrosis, which is of great importance in maintaining cellular homeostasis and delaying the chronic progression of kidney disease. Here, we review the structure and biological function of SIRT6 and summarize the regulatory mechanisms of SIRT6 in kidney disease. Moreover, the role of SIRT6 as a potential therapeutic target for the progression of kidney disease will be discussed. SIRT6 plays an important role in kidney disease. SIRT6 regulates mitochondrial dynamics and mitochondrial biogenesis, induces G2/M cycle arrest, and plays an antioxidant role in nephrotoxicity, IR, obstructive nephropathy, and sepsis-induced AKI. SIRT6 prevents and delays progressive CKD induced by hyperglycemia, kidney senescence, hypertension, and lipid accumulation by regulating mitochondrial biogenesis, and has antioxidant, anti-inflammatory, and antifibrosis effects. Additionally, hypoxia, inflammation, and fibrosis are the main mechanisms of the AKI-to-CKD transition. SIRT6 plays a critical role in the AKI-to-CKD transition and kidney repair through anti-inflammatory, antifibrotic, and mitochondrial quality control mechanisms. AKI Acute kidney injury, CKD Chronic kidney disease.

Mitoquinone Protects Podocytes from Angiotensin II-Induced Mitochondrial Dysfunction and Injury via the Keap1-Nrf2 Signaling Pathway.

Podocyte mitochondrial dysfunction plays a critical role in the pathogenesis of chronic kidney disease (CKD). Previous studies demonstrated that excessive mitochondrial fission could lead to the overproduction of reactive oxygen species (ROS) and promote podocyte apoptosis. Therefore, the maintenance of stable mitochondrial function is a newly identified way to protect podocytes and prevent the progression of CKD. As a mitochondria-targeted antioxidant, mitoquinone (MitoQ) has been proven to be a promising agent for the prevention of mitochondrial injury in cardiovascular disease and Parkinson's disease. The present study examined the effects of MitoQ on angiotensin II- (Ang II-) induced podocyte injury both in vivo and in vitro. Podocyte mitochondria in Ang II-infused mice exhibited morphological and functional alterations. The observed mitochondrial fragmentation and ROS production were alleviated with MitoQ treatment. In vitro, alterations in mitochondrial morphology and function in Ang II-stimulated podocytes, including mitochondrial membrane potential reduction, ROS overproduction, and adenosine triphosphate (ATP) deficiency, were significantly reversed by MitoQ. Moreover, MitoQ rescued the expression and translocation of Nrf2 (nuclear factor E2-related factor 2) and decreased the expression of Keap1 (Kelch-like ECH-associated protein 1) in Ang II-stimulated podocytes. Nrf2 knockdown partially blocked the protective effects of MitoQ on Ang II-induced mitochondrial fission and oxidative stress in podocytes. These results demonstrate that MitoQ exerts a protective effect in Ang II-induced mitochondrial injury in podocytes via the Keap1-Nrf2 signaling pathway.

Creatine promotes cancer metastasis through activation of Smad2/3.

As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers.