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Renal interstitial fibrosis (RIF) is a classic pathophysiological process of chronic kidney disease (CKD). However, the mechanisms underlying RIF remain unclear. The present study found that a novel circular RNA, cirInpp5b, might be involved in RIF by high-throughput sequencing. Subsequent experiments revealed that circInpp5b was reduced in UUO mouse kidney tissues and TGF-β1-treated proximal tubular cells. The overexpression of circInpp5b inhibited RIF in UUO mice and prevented extracellular matrix (ECM) deposition in TGF-β1-treated proximal tubular cells. Furthermore, overexpression of circInpp5b down-regulated the protein level of DDX1. Mechanistically, circInpp5b bound to the DDX1 protein and promoted its lysosomal degradation. Collectively, the findings of our study demonstrate that circInpp5b ameliorates RIF by binding to the DDX1 protein and promoting its lysosomal degradation. [ABSTRACT FROM AUTHOR]

Background: Renal interstitial fibrosis (RIF) is a common pathway to end-stage renal disease regardless of the initial etiology. Currently, the molecular mechanisms for RIF remains not fully elucidated. Nuclear receptor subfamily 4 group A member 1(Nr4a1), a member of the NR4A subfamily of nuclear receptors, is a ligand-activated transcription factor. The role of Nr4a1 in RIF remains largely unknown. Methods: In this study, we determined the role and action mechanism of Nr4a1 in RIF. We used unilateral ureteral obstruction (UUO) mice and transforming growth factor (TGF)-β1-treated human renal proximal tubular epithelial cells (HK-2 cells) as in vivo and in vitro models of RIF. A specific Nr4a1 agonist Cytosporone B (Csn-B) was applied to activate Nr4a1 both in vivo and in vitro, and Nr4a1 small interfering RNA was applied in vitro. Renal pathological changes were evaluated by hematoxylin and eosin and Masson staining, and the expression of fibrotic proteins including fibronectin (Fn) and collagen-I (Col-I), and phosphorylated p38 MAPK was measure by immunohistochemical staining and western blot analysis. Results: The results showed that Nr4a1 was upregulated in UUO mouse kidneys, and was positively correlated with the degree of interstitial kidney injury and the levels of fibrotic proteins. Csn-B treatment aggravated UUO-induced renal interstitial fibrosis, and induced p38 MAPK phosphorylation. In vitro, TGF-β induced Nr4a1 expression, and Nr4a1 downregulation prevented TGF-β1-induced expression of Fn and Col-I and the activation of p38 MAPK. Csn-B induced fibrotic proteins expression and p38 MAPK phosphorylation, and moreover Csn-B induced fibrotic proteins expression was abrogated by treatment with p38 MAPK inhibitor SB203580. We provided further evidence that Csn-B treatment promoted cytoplasmic accumulation of Nr4a1. Conclusion: The findings in the present study indicate that Nr4a1 promotes renal fibrosis potentially through activating p38 MAPK kinase. [ABSTRACT FROM AUTHOR]

Cisplatin is an effective chemotherapeutic agent for various solid tumours, but its use is limited by adverse effects in normal tissues. In particular, cisplatin is nephrotoxic and can cause acute kidney injury and chronic kidney disease. Preclinical studies have provided insights into the cellular and molecular mechanisms of cisplatin nephrotoxicity, which involve intracellular stresses including DNA damage, mitochondrial pathology, oxidative stress and endoplasmic reticulum stress. Stress responses, including autophagy, cell-cycle arrest, senescence, apoptosis, programmed necrosis and inflammation have key roles in the pathogenesis of cisplatin nephrotoxicity. In addition, emerging evidence suggests a contribution of epigenetic changes to cisplatin-induced acute kidney injury and chronic kidney disease. Further research is needed to determine how these pathways are integrated and to identify the cell type-specific roles of critical molecules involved in regulated necrosis, inflammation and epigenetic modifications in cisplatin nephrotoxicity. A number of potential therapeutic targets for cisplatin nephrotoxicity have been identified. However, the effects of renoprotective strategies on the efficacy of cisplatin chemotherapy needs to be thoroughly evaluated. Further research using tumour-bearing animals, multi-omics and genome-wide association studies will enable a comprehensive understanding of the complex cellular and molecular mechanisms of cisplatin nephrotoxicity and potentially lead to the identification of specific targets to protect the kidney without compromising the chemotherapeutic efficacy of cisplatin. Here, the authors review the mechanisms that underlie cisplatin-induced acute kidney injury and chronic kidney disease. They also discuss the challenges of developing renoprotective approaches for patients receiving cisplatin-based chemotherapy and potential targets for renoprotection. Key points: Cisplatin is nephrotoxin that can cause both acute kidney injury and chronic kidney disease. Accumulation of cisplatin in renal tubular cells induces various intracellular stresses, including DNA damage, mitochondrial pathology, oxidative stress and endoplasmic reticulum stress. Multiple stress responses, including autophagy, cell-cycle arrest, senescence, apoptosis, programmed necrosis and inflammation, have important roles in the pathogenesis of cisplatin nephrotoxicity. Epigenetic mechanisms, including histone acetylation, DNA and messenger RNA methylation and gene regulation by non-coding RNAs also contribute to cisplatin nephrotoxicity. How the various cellular stresses and pathways are integrated and the cell type-specific roles of critical molecules involved in regulated necrosis, inflammation and epigenetic modifications in cisplatin nephrotoxicity remain to be determined. Renoprotective strategies for cisplatin nephrotoxicity have been identified in preclinical studies; however, their effects on the efficacy of cisplatin-mediated cancer therapy in animal models must be evaluated before clinical translation. [ABSTRACT FROM AUTHOR]

Mitochondria are essential for the activity, function and viability of eukaryotic cells and mitochondrial dysfunction is involved in the pathogenesis of acute kidney injury (AKI) and chronic kidney disease, as well as in abnormal kidney repair after AKI. Multiple quality control mechanisms, including antioxidant defence, protein quality control, mitochondrial DNA repair, mitochondrial dynamics, mitophagy and mitochondrial biogenesis, have evolved to preserve mitochondrial homeostasis under physiological and pathological conditions. Loss of these mechanisms may induce mitochondrial damage and dysfunction, leading to cell death, tissue injury and, potentially, organ failure. Accumulating evidence suggests a role of disturbances in mitochondrial quality control in the pathogenesis of AKI, incomplete or maladaptive kidney repair and chronic kidney disease. Moreover, specific interventions that target mitochondrial quality control mechanisms to preserve and restore mitochondrial function have emerged as promising therapeutic strategies to prevent and treat kidney injury and accelerate kidney repair. However, clinical translation of these findings is challenging owing to potential adverse effects, unclear mechanisms of action and a lack of knowledge of the specific roles and regulation of mitochondrial quality control mechanisms in kidney resident and circulating cell types during injury and repair of the kidney. [ABSTRACT FROM AUTHOR]

Autophagy is a conserved lysosomal pathway for the degradation of cytoplasmic components. Basal autophagy in kidney cells is essential for the maintenance of kidney homeostasis, structure and function. Under stress conditions, autophagy is altered as part of the adaptive response of kidney cells, in a process that is tightly regulated by signalling pathways that can modulate the cellular autophagic flux - mammalian target of rapamycin, AMP-activated protein kinase and sirtuins are key regulators of autophagy. Dysregulated autophagy contributes to the pathogenesis of acute kidney injury, to incomplete kidney repair after acute kidney injury and to chronic kidney disease of varied aetiologies, including diabetic kidney disease, focal segmental glomerulosclerosis and polycystic kidney disease. Autophagy also has a role in kidney ageing. However, questions remain about whether autophagy has a protective or a pathological role in kidney fibrosis, and about the precise mechanisms and signalling pathways underlying the autophagy response in different types of kidney cells and across the spectrum of kidney diseases. Further research is needed to gain insights into the regulation of autophagy in the kidneys and to enable the discovery of pathway-specific and kidney-selective therapies for kidney diseases and anti-ageing strategies. [ABSTRACT FROM AUTHOR]

Abstract Acute kidney injury (AKI) is a major kidney disease with poor clinical outcome. Besides its acute consequence of high mortality, AKI may also contribute significantly to the occurrence and progression of chronic kidney diseases (CKD). Accumulating evidence has demonstrated that maladaptive and incomplete kidney repair after AKI leads to the development of renal fibrosis and, ultimately, CKD. p53, a well-known tumor suppressor, plays a critical role in AKI and subsequent kidney repair through the regulation of various cell biologic processes, including apoptosis, cell cycle arrest, and autophagy. Despite the notable progress in deciphering the involvement of p53 in kidney injury and repair, the underlying mechanisms of p53 in these pathological processes remain largely unknown. Further investigation in this area is essential for the application of p53 as therapeutic target to prevent and treat AKI or impede its progression to CKD. In this review, we summarize the recent advances in understanding p53 regulation of AKI and kidney repair, pinpoint the potential of p53 as a therapeutic target, and present future research interests and directions. [ABSTRACT FROM AUTHOR]

DNA damage activates specific cell signaling cascades for DNA repair, cell cycle arrest, senescence, and/or cell death. Recent studies have demonstrated DNA damage response (DDR) in experimental models of acute kidney injury (AKI). In cisplatin-induced AKI or nephrotoxicity, the DDR pathway of ATR/Chk2/p53 is activated and contributes to renal tubular cell apoptosis. In ischemic AKI, DDR seems more complex and involves at least the ataxia telangiectasia mutated (ATM), a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, and p53; however, while ATM may promote DNA repair, p53 may trigger cell death. Targeting DDR for kidney protection in AKI therefore relies on a thorough elucidation of the DDR pathways in various forms of AKI. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms have been implicated in the pathogenesis of renal diseases, including acute kidney injury (AKI). Mar et al. now unravel the acetylation and methylation at histones that are associated with the transcription of key genes in AKI. Notably, histone modifications display a remarkable heterogeneity in ischemic and endotoxic AKI. Targeting epigenetic programs may offer novel strategies to protect kidneys from AKI and enhance kidney repair and recovery. [ABSTRACT FROM AUTHOR]

Fragile X associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder caused by aberrant expansion of CGG repeats in 5′ UTR of FMR1 gene. The elevated mRNA confers a toxic gain-of-function thought to be the critical event of pathogenesis. Expressing rCGG90 repeats of the human FMR1 5′UTR in Drosophila is sufficient to induce neurodegeneration. Rapamycin has been demonstrated to attenuate neurotoxicity by inducing autophagy in various animal models of neurodegenerative diseases. Surprisingly, we observed rapamycin exacerbated rCGG90-induced neurodegenerative phenotypes through an autophagy-independent mechanism. CGG90 expression levels of FXTAS flies exposed to rapamycin presented no significant differences. We further demonstrated that activation of the mammalian target of rapamycin (mTOR) signaling could suppress neurodegeneration of FXTAS. These findings indicate that rapamycin will exacerbate neurodegeneration, and that enhancing autophagy is insufficient to alleviate neurotoxicity in FXTAS. Moreover, these results suggest mTOR and its downstream molecules as new therapeutic targets for FXTAS by showing significant protection against neurodegeneration. [ABSTRACT FROM AUTHOR]

The structure of CsPbI3 nanocrystals (NCs) with excellent photoelectric properties easily collapses, which hinders their application in light-emitting diodes (LEDs). Herein, we accomplished the synthesis of efficient and stable CsPbI3 NCs by regulating structural rigidity under the synergistic effect of Mg2+ and AcO− ions. The introduced AcO− and Mg2+ ions increase surface steric hindrance and defect formation energy, which enhances the structural rigidity of the perovskite. As a result, the CsPbI3 NCs display an outstanding photoluminescence quantum yield of 95.7%, in conjunction with reduced defect state density, balanced carrier injection, and distinguished conductivity. Remarkably, the modified CsPbI3 NCs exhibit excellent stability under ambient conditions for 180 days and can even survive when the temperature reaches 150 °C. Given their enhanced structural rigidity, LEDs made from these modified CsPbI3 NCs exhibit a maximum luminance and an EQE of 3281 cd m−2 and 13.2%, respectively, which are significantly improved compared with those of unmodified CsPbI3 NC LEDs. [ABSTRACT FROM AUTHOR]

Epigenetic regulation, which is characterized by reversible and heritable genetic alterations without changing DNA sequences, has recently been increasingly studied in diseases. Histone variant regulation is an essential component of epigenetic regulation. The substitution of canonical histones by histone variants profoundly alters the local chromatin structure and modulates DNA accessibility to regulatory factors, thereby exerting a pivotal influence on gene regulation and DNA damage repair. Histone H2A variants, mainly including H2A.Z, H2A.B, macroH2A, and H2A.X, are the most abundant identified variants among all histone variants with the greatest sequence diversity. Harboring varied chromatin occupancy and structures, histone H2A variants perform distinct functions in gene transcription and DNA damage repair. They are implicated in multiple pathophysiological mechanisms and the emergence of different illnesses. Cancer, embryonic development abnormalities, neurological diseases, metabolic diseases, and heart diseases have all been linked to histone H2A variant alterations. This review focuses on the functions of H2A histone variants in mammals, including H2A.Z, H2A.B, macroH2A, and H2A.X, and their current roles in various diseases. [ABSTRACT FROM AUTHOR]

Objectives: Conventional glucocorticoid (GC) treatment poses significant risks for opportunistic infections due to its suppressive impact on CD4+ T cells. This study aimed to explore the mechanisms by which GCs modulate the functionality of CD4+ T cells during infection. Methods: We consistently measured FOXP3, inflammatory cytokines and phospho‐S6 ribosomal protein levels in CD4+ T cells from patients undergoing conventional GC treatment. Using Foxp3EGFP animals, we investigated the dynamic activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and its correlation with the immunoregulatory function of CD4+ T cells under the influence of GCs. Results: GCs dynamically altered the expression pattern of FOXP3 in CD4+ T cells, promoting their acquisition of an active T regulatory (Treg) cell phenotype upon stimulation. Mechanistically, GCs undermined the kinetics of the mTORC1 pathway, which was closely correlated with phenotype conversion and functional properties of CD4+ T cells. Dynamic activation of the mTORC1 signaling modified the GC‐dampened immunoregulatory capacity of CD4+ T cells by phenotypically and functionally bolstering the FOXP3+ Treg cells. Interventions targeting the mTORC1 pathway effectively modulated the GC‐dampened immunoregulatory capacity of CD4+ T cells. Conclusion: These findings highlight a novel mTORC1‐mediated mechanism underlying CD4+ T cell immunity in the context of conventional GC treatment. [ABSTRACT FROM AUTHOR]

Background: Septic acute kidney injury (S-AKI) is the leading form of acute kidney failure among hospitalized patients, and the inflammatory response is involved in this process. 4-octyl itaconate (4-OI) is a multi-target itaconate derivative with potent anti-inflammatory action. However, it remains elusive whether and how 4-OI contributes to the regulation of S-AKI. Methods: We employed a lipopolysaccharide (LPS)-induced AKI murine model and explored the potential renoprotective effect of 4-OI in vivo. In vitro experiments, BUMPT cells, a murine renal tubular cell line, were conducted to examine the effects of 4-OI on inflammation, oxidative stress, and mitophagy. Moreover, STAT3 plasmid was transfected in BUMPT cells to investigate the role of STAT3 signaling in the 4-OI-administrated state. Results: We demonstrate that 4-OI protects against S-AKI through suppressing inflammation and oxidative stress and enhancing mitophagy. 4-OI significantly reduced the levels of Scr, BUN, Ngal as well as the tubular injury in LPS-induced AKI mice. 4-OI restrained inflammation by reducing macrophage infiltration and suppressing the expression of IL-1β and NLRP3 in the septic kidney. 4-OI also reduced ROS levels, as well as cleaved caspase-3 and boosted antioxidants such as HO-1, and NQO1 in mice. In addition, the 4-OI treatment significantly promoted mitophagy. Mechanistically, 4-OI activated Nrf2 signaling and suppressed phosphorylated STAT3 in vivo and vitro. Molecular docking revealed the binding affinity of 4-OI towards STAT3. ML385, a specific Nrf2 inhibitor, partially repressed the anti-inflammatory and anti-oxidative effects of 4-OI and partially restricted the mitophagy induced by 4-OI in vivo and in vitro. Transfected with STAT3 plasmid partially suppressed mitophagy and the anti-inflammatory effect provoked by 4-OI in vitro. Conclusion: These data suggest that 4-OI ameliorates LPS-induced AKI by suppressing inflammation and oxidative stress and enhancing mitophagy through the overactivation of the Nrf2 signaling pathway, and inactivation of STAT3. Our study identifies 4-OI as a promising pharmacologic for S-AKI. [ABSTRACT FROM AUTHOR]

Background Acute kidney injury (AKI) is a public health problem with no specific therapies in the clinic and the underlying pathogenesis of AKI remains obscure. Bombesin receptor-activated protein (BRAP, C6ORF89 protein) was initially discovered as a ligand for a previously orphan G-protein-coupled receptor bombesin-like receptor-3. At present, accepted biological effects of BRAP include cell cycle progression, wound repair and the activation of histone deacetylases. However, its role in kidney disease is unknown. In this study we have investigated the role of BRAP and underlying mechanisms involved in cisplatin (CP)-induced AKI. Methods Here we used Bc004004 (homologous of C6ORF89 in mice) knockout mice and HK2 cells to investigate the effect of BRAP on AKI in vitro and in vivo. We analyzed ChIP-Seq and RNA-Seq data to search for the upstream regulators of BRAP and downstream mediators of BRAP action in AKI. Immunostaining, real-time polymerase chain reaction (PCR), co-immunoprecipitation, a dual-luciferase reporter assay and ChIP-PCR assay were applied to reveal the upstream and downstream regulation mechanism of BRAP during cisplatin-induced AKI. Results BRAP was downregulated in mice and human kidneys with AKI. Global Bc004004 deletion alleviated tubular cell apoptosis and necroptosis in CP-induced AKI mice, whereas local overexpression of BRAP in kidneys aggravated them. Pan-caspase inhibitor Z-VAD pretreatment attenuated CP-induced blood creatinine increase and kidney injury in wild-type mice but not in BRAP -/- mice. The activation of mixed lineage kinase like-domain was magnified by Z-VAD in CP-treated mice, especially in BRAP -/- mice. The cytoprotective effect of Z-VAD was more substantial than necrostatin-1 (Nec-1, an inhibitor of necroptosis) in CP-treated human kidney proximal tubular epithelial (HK2) cells. Furthermore, Nec-1 pretreatment reduced the CP-induced cell death in BRAP overexpression HK2 cells but did not work in cells with normal BRAP levels. We determined that CP treatment activated the nuclear factor-κB subunit P65 and inhibition of P65 increased the messenger RNA (mRNA) levels of BRAP in HK2 cells. The chromatin immunoprecipitation assay and dual-luciferase reporter gene assay verified P65 binding to the C6ORF89 promoter and reduced its mRNA expression upon CP treatment. Next we found that sirtuin 2 (SIRT2) was downregulated in CP-induced AKI and BRAP levels directly impacted the protein levels of SIRT2. Our findings further confirmed that BRAP regulates the SIRT2 protein levels by affecting SIRT2's interactions with E3 ubiquitin ligase HRD1 and subsequent proteasomal degradation. Conclusions Our results demonstrated that BRAP played an important role in tubular cell apoptosis and necroptosis during CP-induced AKI. Safe and efficient BRAP inhibitors might be effective therapeutic options for AKI. [ABSTRACT FROM AUTHOR]

Cisplatin and its derivatives are widely used chemotherapeutic drugs for cancer treatment. However, they have debilitating side effects in normal tissues and induce ototoxicity, neurotoxicity, and nephrotoxicity. In kidneys, cisplatin preferentially accumulates in renal tubular cells causing tubular cell injury and death, resulting in acute kidney injury (AKI). Recent studies have suggested that DNA damage and the associated DNA damage response (DDR) are an important pathogenic mechanism of AKI following cisplatin treatment. Activation of DDR may lead to cell cycle arrest and DNA repair for cell survival or, in the presence of severe injury, kidney cell death. Modulation of DDR may provide novel renoprotective strategies for cancer patients undergoing cisplatin chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD. Methods: Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2−/− mice) and the control mice (Pacs-2fl/fl mice). Transcriptomic analysis was performed between Pacs-2fl/fl mice and PT-Pacs-2−/− mice. Results: Diabetic PT-Pacs-2−/− mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2fl/fl mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2−/− mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA. Conclusions: PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling. [ABSTRACT FROM AUTHOR]

Background: Mesangial cell proliferation is the most basic pathological feature of immunoglobulin A nephropathy (IgAN); however, the specific underlying mechanism and an appropriate therapeutic strategy are yet to be unearthed. This study aimed to investigate the therapeutic effect of triptolide (TP) on IgAN and the mechanism by which TP regulates autophagy and proliferation of mesangial cells through the CARD9/p38 MAPK pathway. Methods: We established a TP‐treated IgAN mouse model and produced IgA1‐induced human mesangial cells (HMC) and divided them into control, TP, IgAN, and IgAN+TP groups. The levels of mesangial cell proliferation (PCNA, cyclin D1, cell viability, and cell cycle) and autophagy (P62, LC3 II, and autophagy flux rate) were measured, with the autophagy inhibitor 3‐Methyladenine used to explore the relationship between autophagy and proliferation. We observed CARD9 expression in renal biopsies from patients and analyzed its clinical significance. CARD9 siRNA and overexpression plasmids were constructed to investigate the changes in mesangial cell proliferation and autophagy as well as the expression of CARD9 and p‐p38 MAPK/p38 MAPK following TP treatment. Results: Administering TP was safe and effectively alleviated mesangial cell proliferation in IgAN mice. Moreover, TP inhibited IgA1‐induced HMC proliferation by promoting autophagy. The high expression of CARD9 in IgAN patients was positively correlated with the severity of HMC proliferation. CARD9/p38 MAPK was involved in the regulation of HMC autophagy and proliferation, and TP promoted autophagy to inhibit HMC proliferation by downregulating the CARD9/p38 MAPK pathway in IgAN. Conclusion: TP promotes autophagy to inhibit mesangial cell proliferation in IgAN via the CARD9/p38 MAPK pathway. [ABSTRACT FROM AUTHOR]

Background: Cisplatin is an effective chemotherapeutic drug, but it may induce both acute and chronic kidney problems. The pathogenesis of chronic kidney disease (CKD) associated with cisplatin chemotherapy remains largely unclear. Methods: Mice and renal tubular cells were subjected to repeated low-dose cisplatin (RLDC) treatment to induce CKD and related pathological changes. The roles of endoplasmic reticulum (ER) stress, PERK, and protein kinase C-δ (PKCδ) were determined using pharmacological inhibitors and genetic manipulation. Results: ER stress was induced by RLDC in kidney tubular cells in both in vivo and in vitro models. ER stress inhibitors given immediately after RLDC attenuated kidney dysfunction, tubular atrophy, kidney fibrosis, and inflammation in mice. In cultured renal proximal tubular cells, inhibitors of ER stress or its signaling kinase PERK also suppressed RLDC-induced fibrotic changes and the expression of inflammatory cytokines. Interestingly, RLDC-induced PKCδ activation, which was blocked by ER stress or PERK inhibitors, suggesting PKCδ may act downstream of PERK. Indeed, suppression of PKCδ with a kinase-dead PKCδ (PKCδ-KD) or Pkcδ-shRNA attenuated RLDC-induced fibrotic and inflammatory changes. Moreover, the expression of active PKCδ-catalytic fragment (PKCδ-CF) diminished the beneficial effects of PERK inhibitor in RLDC-treated cells. Co-immunoprecipitation assay further suggested PERK binding to PKCδ. Conclusion: These results indicate that ER stress contributes to chronic kidney pathologies following cisplatin chemotherapy via the PERK–PKCδ pathway. [ABSTRACT FROM AUTHOR]

Flexible perovskite light‐emitting diodes (LEDs) have been highly expected to realize advanced wearable optoelectronic applications due to the excellent optoelectronic properties of perovskites. However, the poor water and oxygen stability and limited flexibility of perovskites prevent their commercialization and applications in flexible LEDs. Herein, the low‐cost and green biomass materials‐ethyl cellulose (EC) is added in the CsPbI3 nanocrystals (NCs), acting as a cross‐linker between neighboring halide octahedra through hydrogen bonds and PbO coordination bonds. It reduces the defect densities of NCs, leading to improved photoluminescence quantum yield. Simultaneously, the synergistic effect of efficient defect passivation and hydrophobic ether groups of EC significantly improve the environment stability of NCs. Additionally, the favorable flexibility of EC and cross‐linking between EC and perovskite NCs improve the deformation resistance of the perovskite layer with stable photoluminescence and negligible cracks after repeated bending. Consequently, flexible LEDs based on the EC‐passivated CsPbI3 NCs achieved a record external quantum efficiency of 12.1% and significantly enhanced operational stability. Moreover, the flexible LEDs show small luminance degradation after bending for 1000 cycles at a radius of 3 mm, and still retain high performance even after repeatedly bending at an ultrasmall bending radius of 1 mm. [ABSTRACT FROM AUTHOR]

Lipoapoptosis in Proximal tubular epithelial cells (PTCs) are substantial in the etiology of diabetic kidney disease (DKD), yet the underlying mechanisms warrant further investigation. Acyl-CoA synthetase long-chain family member 5 (ACSL5) facilitates the formation of acyl-CoA, however, the precise role of ACSL5 in lipoapoptosis of PTCs in DKD remains inconclusive. Transcriptomic data analysis identified the hub gene Acsl5 associated with lipid metabolism in DKD. The expression of ACSL5 was examined in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice and high glucose/palmitic acid (HGPA)-induced mouse proximal tubular epithelial cell (BUMPT). Oil Red O staining, free fatty acids (FFA) ELISA assay, Western Blot, and morphological changes were employed to assess lipid deposition and lipoapoptosis. Furthermore, knockdown and overexpression of ACSL5 were conducted in BUMPT cells, followed by morphological assessment, Oil Red O staining, FFA ELISA assay and Western Blot analysis. Using the ChEA3 database, we predicted that STAT3 may transcriptionally regulate ACSL5. Subsequently, we knocked down STAT3 and evaluated Acsl5 expression via RT-qPCR. Additionally, we investigated whether STAT3 modulates the impact of ACSL5 on lipoapoptosis through Western Blot analysis. We demonstrated, for the first time, a notable upregulation of ACSL5 expression in PTCs in HFD/STZ-induced diabetic mice, accompanied by increased the expression of FATP2, lipid accumulation and heightened lipoapoptosis. In HGPA-treated BUMPT cells, ACSL5 knockdown reduced the expression of FATP2, lipid deposition and lipoapoptosis, whereas its overexpression elevated the expression of FATP2 and exacerbated these effects. These findings strongly suggest that ACSL5 may exacerbate lipoapoptosis in PTCs within a diabetic milieu. From a molecular mechanism perspective, ACSL5 expression decreased after Stat3 knockdown. Concurrent knockdown of Stat3 and overexpression of Acsl5 led to a mitigation of lipoapoptosis compared to sole Acsl5 overexpression. Furthermore, STAT3 promotes the activation of ACSL5 promoter under HGPA conditions. In summary, our research identified ACSL5 as an important contributor exacerbating lipoapoptosis in the renal proximal tubules within diabetic environments. In addition, we found that ACSL5 is transcriptionally regulated by STAT3. • ACSL5 is upregulated in PTCs of diabetic mice, where it plays a critical role in lipid accumulation and lipoapoptosis. • ACSL5 knockdown reduces lipid accumulation and lipoapoptosis in PTCs, whereas its overexpression exacerbates these effects. • ACSL5 promotes FFA uptake by indirectly upregulating FATP2 expression. • ACSL5 is transcriptionally regulated by STAT3 under HGPA condition. [ABSTRACT FROM AUTHOR]

Background: Split hand/foot malformation (SHFM) is a congenital limb developmental disorder, which impairs the fine activities of hand/foot in the affected individuals seriously. SHFM is commonly inherited as an autosomal dominant disease with incomplete penetrance. Chromosomal aberrations such as copy number variations and translocations have been linked to SHFM. This study aimed to identify the genetic cause for three patients with bilateral hand and foot malformation in a Chinese family. Methods: Karyotyping, single‐nucleotide polymorphism (SNP) array, whole exome sequencing, whole genome sequencing, and Sanger sequencing were applied to identify the pathogenic variant. Results: Karyotyping revealed that the three patients had balanced reciprocal translocation, 46, XX, t(3;15) (q29;q22). SNP array identified no pathogenic copy number variation in the proband. Trio‐WES (fetus–mother–father) sequencing results revealed no pathogenic variants in the genes related to SHFM. Whole‐genome low‐coverage mate‐pair sequencing (WGL‐MPS), breakpoint PCR, and Sanger sequencing identified the breakpoints disrupting TP63 in the patients, but not in healthy family members. Conclusion: This study firstly reports that a translocation breakpoint disrupting TP63 contributes to the SHFM in a Chinese family, which expands our knowledge of genetic risk and counseling underlying SHFM. It provides a basis for genetic counseling and prenatal diagnosis (preimplantation genetic diagnosis) for this family. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a major kidney disease characterized by rapid decline of renal function. Besides its acute consequence of high mortality, AKI has recently been recognized as an independent risk factor for chronic kidney disease (CKD). Maladaptive or incomplete repair of renal tubules after severe or episodic AKI leads to renal fibrosis and, eventually, CKD. Recent studies highlight a key role of mitochondrial pathology in AKI development and abnormal kidney repair after AKI. As such, timely elimination of damaged mitochondria in renal tubular cells represents an important quality control mechanism for cell homeostasis and survival during kidney injury and repair. Mitophagy is a selective form of autophagy that selectively removes redundant or damaged mitochondria. Here, we summarize our recent understanding on the molecular mechanisms of mitophagy, discuss the role of mitophagy in AKI development and kidney repair after AKI, and present future research directions and therapeutic potential. [ABSTRACT FROM AUTHOR]

Background: This study aimed to define the molecular basis for 12 prenatal cases of Cri‐du‐chat syndrome (CdCS) and the potential genotyping‐phenotyping association. Methods: Karyotyping and single nucleotide polymorphism array analyses for copy number variants were performed. Results: Nine cases had 5p terminal deletions and three had 5p interstitial deletions, and these cases had variable deletion sizes with partial overlapping. Phenotypically, besides intrauterine growth restriction (IUGR) and brain as well as heart abnormalities, hypospadias, and lung dysplasia were observed. Potential genetic causes for specific phenotypes in these cases were identified. Conclusion: This study defined the molecular bases for the patients of CdCS, which is important for genetic counseling for these families. The findings of present study expand the clinical features of CdCS in the fetal period, and provided important information for further refining the genotypic–phenotypic correlations for this syndrome. [ABSTRACT FROM AUTHOR]

Norcantharidin (NCTD) is a potential anti-renal interstitial fibrotic drug. However, the underlying molecular mechanism of how NCTD works remains unclear. In this study, using both in vivo and in vitro models, we report that the level of β-catenin is positively correlated to the degree of renal interstitial fibrosis (RIF). Protein phosphatase 2A (PP2A) binds to β-catenin and suppresses its phosphorylation, thereby increasing the total β-catenin expression. Additionally, NCTD dramatically elevates the level of phosphorylated β-catenin and decreases total β-catenin expression in a dose-dependent manner, consequently leading to the reduction of RIF. Mechanistically, PP2A-mediated suppression of β-catenin phosphorylation is an essential target for the anti-renal interstitial fibrotic effect of NCTD. Therefore, we report a potential theoretical basis for clinical application of NCTD in treating RIF. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is an essential cause of kidney failure and end-stage kidney disease worldwide. Mesangial hypercellularity is an important characteristic of IgAN, but the underlying mechanism remains unclear. Endoplasmic reticulum (ER) stress is a series of stress responses to restore the function of endoplasmic reticulum. We aimed to explore how ER stress functioned in kidneys of IgAN. We first examined ER stress in IgAN kidneys in vivo and in vitro, by testing the levels of ER stress associated proteins (BIP, p-eIF2α and ATF4). Our results showed that ER stress was activated in IgAN patients, mice and cell model. ER stress activation was related to the distribution of IgA deposition and the degree of mesangial proliferation. To determine the role of ER stress in mesangial cell (MC) proliferation of IgAN, we then tested the levels of ER stress and MC proliferation (cyclin D1, cell viability and cell cycle) through inhibiting ER stress associated proteins. After inhibiting ER stress associated proteins, ER stress was inactivated and cell proliferation was inhibited in MCs. We also explored the correlation between ER stress in the glomerulus and the clinical outcomes of IgAN patients in a prospective study. Patients with lower expression of p-eIF2α or ATF4 had higher rates of hematuria remission, proteinuria remission and clinical remission. In summary, our work outlines that in IgAN, ER stress mediated by eIF2α/ATF4 pathway promotes MC proliferation via up-regulating the expression of cyclin D1. Furthermore, p-eIF2α and ATF4 in the glomerulus negatively correlate with the clinical remission of IgAN patients. • Endoplasmic reticulum (ER) stress was activated in IgAN kidneys, especially in mesangial cells, and was positively correlated with mesangial cell proliferation. • When ER stress was inhibited, the proliferation of pIgA1-induced mesangial cells was inhibited. • ER stress associated proteins, p-eIF2α and ATF4 in the glomerulus, were negatively correlated with the clinical remission of IgAN patients. • EIF2α/ATF4/cyclin D1 axis was activated in IgAN leading to mesangial cell proliferation. [ABSTRACT FROM AUTHOR]

Objectives The association between interstitial fibrosis and tubular atrophy (IFTA) and the clinical outcomes in diabetic nephropathy (DN) remains unclear. This study is to evaluate the clinical predictors and renal prognosis of IFTA score in patients with DN. Methods 52 cases with DN with renal biopsy were divided into three groups according to IFTA score. The χ 2 test or Fisher’s exact test, Mann–Whitney U-test, Kruskal–Wallis H-test and Spearman’s correlation analysis were used in this subject. Ordinal regression mode was utilized to evaluate which clinical factors might be the predictors of IFTA score. Results Compared to IFTA score 1 group, the patients in score 3 were younger and have greatly lower level of eGFR and hemoglobin and higher serum creatinine (p < 0.01). A close relationship between the clinical findings and IFTA was observed, such as IFTA with eGFR(r = − 0.58, P < 0.01), triglyceride(r = − 0.29, P = 0.04), Hb (r = − 0.38, P < 0.01), systolic blood pressure (r = 0.29, P = 0.04) and urinary protein level (r = 0.46, P < 0.01); in addition, eGFR (OR 0.31 (95%Cl − 1.883 to − 0.485) p = 0.001) showed statistical significance with IFTA. The 5-year renal survival rate was estimated as 100% in IFTA score 0, 88.9% in score 1, 76.9% in score 2, and 20.0% in score 3. Furthermore, greatly lower level of eGFR, and higher serum creatinine and BUN in the glomerular class IV were seen (p < 0.01 vs class II), with positive correlation with IFTA (r = 0.51, P < 0.01). Conclusion The renal pathologic diagnosis in IFTA score was a good predictor for renal prognosis in type II DM. eGFR might be a predictor of IFTA in patients with DN. [ABSTRACT FROM AUTHOR]

The deacetylase Sirtuin 6 (SIRT6) is up-regulated during fibrogenesis in renal tubular cells and post-ischemia/reperfusion kidneys. Hence, our aim was to investigate the mechanism of SIRT6 up-regulation upon profibrotic stress. Immunohistochemical staining was used to detect the expression of UBC9 in the kidney section. The interaction of GSK-3β and SIRT6, and phosphorylation level of SIRT6 were detected by the immunoprecipitation assay. The wild-type and phosphorylated site mutant plasmids of SIRT6 were constructed and stably transfected to BUMPT cells to evaluate the phosphorylation function of SIRT6 by immunoblotting assay. The phosphorylation of SIRT6 is significantly increased during TGF-β treatment in mouse renal tubular cells. GSK-3β can physically interact with SIRT6 in renal tubular cells, and this interaction is enhanced by TGF-β treatment. Moreover, GSK-3β is the phosphorylation kinase for SIRT6, and phosphorylates SIRT6 at Serine 326 residue to prevent its ubiquitination-mediated proteasomal degradation. Non-phosphorylatable mutant, S326A, of SIRT6, restores β-catenin activation and fibrotic changes in renal tubular cells. The present study demonstrates that a new mechanism for GSK-3β-mediated anti-fibrotic function in renal fibrosis through phosphorylation of SIRT6 to prevent its proteasomal degradation. [Display omitted] [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is the finding of immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy. Recently studies show that inflammation may involve in the progression of renal glomerulosclerosis and tubulointerstitial scarring in IgAN. This study was designed to evaluate the renoprotective effect of triptolide on IgAN rat model. IgAN was induced in Sprague–Dawley rats by oral and intravenous immunization with BSA for 12 weeks. Rats were treated with triptolide (200 μg/kg/d intragastrically) from 12 to 28 weeks. At Week 28, the rats was sacrificed, kidneys and blood samples were collected for further analysis. Our data shown that IgAN rat model showed marked deterioration of proteinuria together with higher levels of the urine protein:creatinine ratio compared to the normal control. Animals that underwent intermittent exposure to triptolide treatment exhibited significant improvements in the functional parameters without severe side effects. Rats developing IgAN had profound mesangial proliferation and mesangial expansion, intense and diffuse glomerular IgA deposition, while triptolide treatment significantly attenuated it. We also observed that treatment with triptolide significantly decreases serum levels of IL-1β and IL-18, and may exerted anti-inflammatory effects by down-regulating NLRP3 and TLR4 expression. Our study clearly demonstrated that triptolide prevents IgAN progression via an amelioration of inflammasome-mediated proinflammatory cytokine production, thus brought a light of hope for treatment of IgAN. [ABSTRACT FROM AUTHOR]

Background: Gentamicin-induced nephrotoxicity is one of the most common causes of acute kidney injury (AKI). The phenotypic alterations that contribute to acute kidney injury include inflammatory response and oxidative stress. Curcumin has a wide range biological functions, especially as an antioxidant. This study was designed to evaluate the renoprotective effects of curcumin treatment in gentamicin-induced AKI. Methods: Gentamicin-induced AKI was established in female Sprague-Dawley rats. Rats were treated with curcumin (100 mg/kg body mass) by intragastric administration, once daily, followed with an intraperitoneal injection of gentamicin sulfate solution at a dose of 80 mg/kg body mass for 8 consecutive days. At days 3 and 8, the rats were sacrificed, and the kidneys and blood samples were collected for further analysis. Results: The animals treated with gentamicin showed marked deterioration of renal function, together with higher levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) in the plasma as compared with the controls. Animals that underwent intermittent treatment with curcumin exhibited significant improvements in renal functional parameters. We also observed that treatment with curcumin significantly attenuated renal tubular damage, apoptosis, and oxidative stress. Curcumin treatment exerted anti-apoptosis and anti-oxidative effects by up-regulating Nrf2/HO-1 and Sirt1 expression. Conclusions: Our data clearly demonstrate that curcumin protects kidney from gentamicin-induced AKI via the amelioration of oxidative stress and apoptosis of renal tubular cells, thus providing hope for the amelioration of gentamicin-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

Cisplatin is a commonly used anti-cancer drug, but it induces nephrotoxicity. As a water-soluble vitamin B family member, nicotinamide (NAM) was recently demonstrated to have beneficial effects for renal injury, but its underlying mechanism remains largely unclear. Here, we suggest that NAM may exert protective effects against cisplatin-induced acute kidney injury (AKI) mainly via suppressing the poly ADP-ribose polymerase 1 (PARP1)/p53 pathway. In our experiment, NAM protected against cisplatin-induced apoptosis both in cultured renal proximal tubular cells and AKI in mice. Mechanistically, NAM suppressed the expression and activation of p53, a known mediator of cisplatin-induced AKI. Upstream of p53, NAM attenuated the induction of γ-H2AX, a hallmark of DNA damage response. Interestingly, PARP1 was activated in cisplatin AKI and this activation was inhibited by NAM. Pharmacological inhibition of PARP1 with PJ34 significantly ameliorated p53 activation and cisplatin-induced cell death in RPTCs and AKI in mice. Thus, NAM may protect against cisplatin-induced AKI by suppressing the PARP1/p53 pathway. • NAM protects against cisplatin-induced acute kidney injury. • NAM affects the expression and activation of PARP1, γ-H2AX, and p53. • NAM may protect kidneys by suppressing the PARP1/P53 pathway. [ABSTRACT FROM AUTHOR]

This study investigated the role and mechanism of action of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in the pathogenesis of renal interstitial fibrosis (RIF), and its involvement in the anti-RIF effect of norcantharidin (NCTD). Mice with unilateral ureteral obstruction and BUMPT mouse proximal tubular cells exposed to transforming growth factor (TGF)-β1 were used as in vivo and in vitro models of RIF, respectively. NCTD was administered to mice by intraperitoneal injection (0.075 mg kg−1·day−1). Hematoxylin–eosin and Masson's trichrome staining were performed to assess pathologic changes in the kidney. Immunohistochemistry, western blotting, and real-time PCR were performed to evaluate the expression of TWEAK and the fibrotic factors fibronectin (FN) and collagen type I (Col-I). The role of TWEAK in RIF and in the anti-RIF effect of NCTD was evaluated by TWEAK overexpression and neutralization with a specific antibody, and specific inhibitor of Mothers against decapentaplegic homolog (Smad)3 (SIS3) was used to examine the involvement of TGF-β1/Smad3 signaling. TWEAK was mainly expressed in renal tubules in mice; the level was markedly elevated in both in vivo and in vitro RIF models. TWEAK overexpression in BUMPT cells increased the levels of phosphorylated Smad3, FN, and Col-I, which were reduced by treatment with SIS3. NCTD suppressed FN and Col-I expression by blocking TWEAK-mediated Smad3 phosphorylation. Upregulation of TWEAK contributes to RIF by promoting Smad3 phosphorylation, while NCTD inhibits this process. [ABSTRACT FROM AUTHOR]

Renal ischemia-reperfusion is a major cause of acute kidney injury, a disease currently without effective treatments. Irisin was initially identified as an important factor produced by muscles to mediate the health benefits of exercise, and recent work has further suggested its protective effect against lung and liver injury. However, the role of Irisin in kidney diseases, including renal ischemia-reperfusion injury (IRI), remains unknown. In the present study, we found that the Irisin precursor, fibronectin type III domain-containing protein 5 (Fndc5), was induced in renal tubules in a mouse model of renal IRI and in cultured mouse renal proximal tubular cells subjected ATP depletion injury. Functionally, silencing Fndc5 in cultured proximal tubular cells increased the sensitivity to ATP depletion-induced apoptosis, whereas both Fndc5 overexpression and supplementation of recombinant Irisin alleviated ATP depletion-induced apoptosis. In vivo, administration of recombinant Irisin dramatically attenuated kidney dysfunction, tissue damage, tubular cell apoptosis, and inflammation during renal IRI in mice. Mechanistically, Irisin suppressed the activation of p53 in renal IRI, a critical factor in tubular cell death. Together, these results indicate that Irisin is induced in renal IRI as a protective mechanism for renal tubular cells, suggesting the therapeutic potential of recombinant Irisin in renal IRI and related kidney diseases. • Renal tubular cells express FNDC5/Irisin, which is induced by renal ischemia-reperfusion. • Upon induction, FNDC5/Irisin protects against tubular cell injury in renal ischemia-reperfusion. • Recombinant Irisin has a therapeutic potential for renal ischemia-reperfusion injury. • FNDC5/Irisin suppresses p53 activation in renal ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a major kidney disease characterized by an abrupt loss of renal function. Accumulating evidence indicates that incomplete or maladaptive repair after AKI can result in kidney fibrosis and the development and progression of chronic kidney disease (CKD). Hypoxia, a condition of insufficient supply of oxygen to cells and tissues, occurs in both acute and chronic kidney diseases under a variety of clinical and experimental conditions. Hypoxia-inducible factors (HIFs) are the "master" transcription factors responsible for gene expression in hypoxia. Recent researches demonstrate that HIFs play an important role in kidney injury and repair by regulating HIF target genes, including microRNAs. However, there are controversies regarding the pathological roles of HIFs in kidney injury and repair. In this review, we describe the regulation, expression, and functions of HIFs, and their target genes and related functions. We also discuss the involvement of HIFs in AKI and kidney repair, presenting HIFs as effective therapeutic targets. [ABSTRACT FROM AUTHOR]