Association of Serum Unsaturated Fatty Acid Patterns with the Risk of Diabetic Nephropathy.

Introduction: Unsaturated fatty acids play an essential role in the progression of diabetic nephropathy (DN). However, previous studies were mainly focused on the role of individual unsaturated fatty acid. The serum unsaturated fatty acid patterns (FAPs) in patients with DN remain to be determined. Methods: A total of 135 patients with DN (DN group) and 322 patients with type II diabetes without nephropathy (non-DN group) were included in this study. Clinical data, serum levels of unsaturated fatty acids, and other laboratory indicators were collected. Multivariate logistic regression was applied to identify risk factors for serum unsaturated fatty acid level in both groups. Serum unsaturated fatty acids were subjected to factor analysis to identify distinct FAPs. Multivariable logistic regression was employed to assess the risk of DN associated with different serum FAPs. Results: After adjusting for confounders, three types of unsaturated fatty acid including C20:5 (eicosapentaenoic acid [EPA]), C22:6 (docosahexaenoic acid [DHA]), and C22:5 n-3 (docosapentaenoic acid n-3) were significantly associated with DN in the population. The odds ratios (ORs) (95% confidence interval [CI]) of DN were 0.583 (0.374, 0.908), 0.826 (0.716, 0.954), and 0.513 (0.298, 0.883), respectively. Factor analysis revealed five major FAPs, among which FAP2 (enriched with EPA and DHA) exhibited a significant inverse association with DN. In the multivariate-adjusted model, the OR (95% CI) was 0.678 (0.493, 0.933). Additionally, a combination of DHA and EPA enriched in FAP2 further decreased extracellular matrix production induced by transforming growth factor beta 1 in podocytes and tubular cells. Conclusions: Our findings suggest that FAP2 which is enriched with DHA and EPA is associated with a reduced risk of DN. This highlights the potential of targeting FAP2 for the patients with DN.

Palmitoyltransferase DHHC9 and acyl protein thioesterase APT1 modulate renal fibrosis through regulating ß-catenin palmitoylation.

palmitoylation, a reversible post-translational modification, is initiated by the DHHC family of palmitoyltransferases and reversed by several acyl protein thioesterases. However, the role and mechanisms for protein palmitoylation in renal fibrosis have not been elucidated. Here we show protein palmitoylation and DHHC9 were downregulated in the fibrotic kidneys of mouse models and chronic kidney disease (CKD) patients. Ablating DHHC9 in tubular cells aggravated, while inducing DHHC9 overexpression with adeno-DHHC9 transfection or iproniazid treatment protected against kidney fibrosis in male mouse models. Mechanistically, DHHC9 palmitoylated ß-catenin, thereby promoted its ubiquitination and degradation. Additionally, acyl protein thioesterase 1 (APT1) was induced in the fibrotic kidneys, which depalmitoylated ß-catenin, increased its abundance and nuclear translocation. Ablating tubular APT1 or inhibiting APT1 with ML348 markedly protected against unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI)-induced kidney fibrosis in male mice. This study reveals the regulatory mechanism of protein palmitoylation in kidney fibrosis.

An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease.

Background: With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community. Methods and Results: Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD. Conclusions: This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases.

Crosstalk between Interleukin-1 Receptor-Like 1 and Transforming Growth Factor-ß Receptor Signaling Promotes Renal Fibrosis

IL-33, a member of the IL-1 family, acts as an alarmin in immune response. Epithelial-mesenchymal transition and transforming growth factor-ß (TGF-ß)­induced fibroblast activation are key events in the development of renal interstitial fibrosis. The current study found increased expression of IL-33 and interleukin-1 receptor-like 1 (IL1RL1, alias ST2), the receptor for IL-33, in human fibrotic renal tissues. In addition, IL-33­ or ST2-deficient mice showed significantly reduced levels of fibronectin, α-smooth muscle actin, and vimentin, and increased E-cadherin levels. In HK-2 cells, IL-33 promotes the phosphorylation of the TGF-ß receptor (TGF-ßR), Smad2, and Smad3, and the production of extracellular matrix (ECM), with reduced expression of E-cadherin. Blocking TGF-ßR signaling or suppressing ST2 expression impeded Smad2 and Smad3 phosphorylation, thereby reducing ECM production, suggesting that IL-33­induced ECM synthesis requires cooperation between the two pathways. Mechanistically, IL-33 treatment induced a proximate interaction between ST2 and TGF-ßRs, activating downstream Smad2 and Smad3 for ECM production in renal epithelial cells. Collectively, this study identified a novel and essential role for IL-33 in promoting TGF-ß signaling and ECM production in the development of renal fibrosis. Therefore, targeting IL-33/ST2 signaling may be an effective therapeutic strategy for renal fibrosis.

UXT attenuates the CGAS-STING1 signaling by targeting STING1 for autophagic degradation.

STING1 (stimulator of interferon response cGAMP interactor 1), the pivotal adaptor protein of CGAS (cyclic GMP-AMP synthase)-STING1 signaling, is critical for type I IFN production of innate immunity. However, excessive or prolonged activation of STING1 is associated with autoinflammatory and autoimmune diseases. Thus, preventing STING1 from over-activation is important to maintain immune homeostasis. Here, we reported that UXT (ubiquitously expressed prefoldin like chaperone), a small chaperone-like protein, was essential to prevent the excessive activation of STING1-mediated type I IFN signaling through autophagic degradation of STING1 via SQSTM1 (sequestosome 1). Upon DNA mimics or cyclic GMP-AMP (cGAMP) stimulation, UXT specifically interacted with STING1 and promoted STING1 degradation through selective macroautophagy/autophagy. Moreover, UXT was required for more efficient autophagic degradation of STING1 by facilitating the interaction of SQSTM1 and STING1. The in vivo role of UXT in attenuating the CGAS-STING1 signaling was further confirmed in the mouse model of DNA-virus infection and the TMPD (2,6,10,14-tetramethylpentadecane)-induced murine lupus model. Intriguingly, the expression of UXT was consistently impaired and exhibited a remarkable inverse correlation with type I IFN signature in the leukocytes and PBMCs (peripheral blood mononuclear cells) of several large SLE (systemic lupus erythematosus) cohorts. Importantly, the replenishment of UXT effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of UXT in autophagic degradation of STING1 to maintain immune homeostasis. UXT might be a potential therapeutic target for alleviating aberrant type I IFNs in autoimmune diseasesAbbreviations: 3-MA: 3-methyladenine; BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic gmp-amp synthase; cKO: conditional knockout; CXCL10: C-X-C motif chemokine ligand 10; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSV-1: herpes simplex virus type 1; HTDNA: herring testes DNA; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNA4: interferon alpha 4; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; ISGs: IFN-stimulated genes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; RNA-seq: RNA sequencing; PBMCs: peripheral blood mononuclear cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic lupus erythematosus; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TMPD: 2,6,10,14-tetramethylpentadecane; UXT: ubiquitously expressed prefoldin like chaperone.

Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis.

The cell-cell interaction between hepatocytes and Kupffer cells (KCs) is crucial for maintaining liver homeostasis, and the loss of KCs and hepatocytes is known to represent a common pathogenic phenomenon in autoimmune hepatitis. Until now, the mechanisms of cell-cell interaction between hepatocytes and KCs involved in immune-mediated hepatitis remains unclear. Here we dissected the impact of activated mTORC1 on the cell-cell interaction of KCs and hepatocyte in immune-mediated hepatitis. In the liver from patients with AIH and mice administrated with Con-A, mTORC1 was activated in both KCs and hepatocytes. The activated mTORC1 signal in hepatocytes with Con-A challenge caused a markedly production of miR-329-3p. Upregulated miR-329-3p inhibited SGMS1 expression in KCs through paracrine, resulting in the death of KCs. Most of maintained KCs were p-S6 positive and distributed in hepatocyte mTORC1 negative area. The activation of mTORC1 enabled KCs expressed complement factor B (CFB) to enhance the complement alternative system, which produced more complement factors to aggravate liver injury. Our findings remonstrate a heterogeneous role of mTORC1 in specific cell type for maintaining tolerogenic liver environment, and will form the basis for the development of new interventions against immune-mediated hepatitis.

Metabolic Regulation of Fibroblast Activation and Proliferation during Organ Fibrosis.

Background: Activated fibroblasts are present in the injury response, tumorigenesis, fibrosis, and inflammation in a variety of tissues and myriad disease types. Summary: During normal tissue repair, quiescent fibroblasts transform into a proliferative and contractile phenotype termed myofibroblasts and are then lost as repair resolves to form a scar. When excessive levels are reached, activated fibroblasts proliferate and produce large amounts of extracellular matrix, which accumulates in the interstitial space of different organs. This accumulation leads to fibrotic dysfunction and multiple-organ dysfunction syndrome. To date, there are limited effective treatments for these conditions. Cellular metabolism is the cornerstone of all biological activities. Emerging evidence shows that metabolic alterations in fibroblasts are important for the activation process and illness progression. These discoveries, along with current clinical advances showing decreased lung fibrosis after targeting specific metabolic pathways, thus offer new possibilities for therapeutic interventions. The purpose of this review was to summarize the most recent knowledge of the major metabolic changes that occur during fibroblast transition from quiescent to activated states and the evidence linking alterations in fibroblast metabolism to the pathobiology of several common fibrotic diseases and tumor-related diseases. Key Messages: Metabolic disorders are associated with the progression of chronic kidney diseases. Interfering with fibroblast metabolism may be a promising therapeutic strategy for renal fibrosis and other fibrosis-related diseases.

Follistatin-like 1 (FSTL1) interacts with Wnt ligands and Frizzled receptors to enhance Wnt/ß-catenin signaling in obstructed kidneys in vivo.

Follistatin (FS)-like 1 (FSTL1) is a member of the FS-SPARC (secreted protein, acidic and rich in cysteine) family of secreted and extracellular matrix proteins. The functions of FSTL1 have been studied in heart and lung injury as well as in wound healing; however, the role of FSTL1 in the kidney is largely unknown. Here, we show using single-cell RNA-Seq that Fstl1 was enriched in stromal cells in obstructed mouse kidneys. In addition, immunofluorescence demonstrated that FSTL1 expression was induced in fibroblasts during kidney fibrogenesis in mice and human patients. We demonstrate that FSTL1 overexpression increased renal fibrosis and activated the Wnt/ß-catenin signaling pathway, known to promote kidney fibrosis, but not the transforming growth factor ß (TGF-ß), Notch, Hedgehog, or Yes-associated protein (YAP) signaling pathways in obstructed mouse kidneys, whereas inhibition of FSTL1 lowered Wnt/ß-catenin signaling. Importantly, we show that FSTL1 interacted with Wnt ligands and the Frizzled (FZD) receptors but not the coreceptor lipoprotein receptor-related protein 6 (LRP6). Specifically, we found FSTL1 interacted with Wnt3a through its extracellular calcium-binding (EC) domain and von Willebrand factor type C-like (VWC) domain, and with FZD4 through its EC domain. Furthermore, we show that FSTL1 increased the association of Wnt3a with FZD4 and promoted Wnt/ß-catenin signaling and fibrogenesis. The EC domain interacting with both Wnt3a and FZD4 also enhanced Wnt3a signaling. Therefore, we conclude that FSTL1 is a novel extracellular enhancer of the Wnt/ß-catenin pathway.

Protein phosphatase 2Acα modulates fatty acid oxidation and glycolysis to determine tubular cell fate and kidney injury.

Energy metabolism is crucial in maintaining cellular homeostasis and adapting to stimuli for tubular cells. However, the underlying mechanisms remain largely unknown. Here, we report that PP2Acα was upregulated in damaged tubular cells from patients and animal models with acute or chronic kidney injury. Using in vitro and in vivo model, we demonstrated that PP2Acα induction in damaged tubular cells suppresses fatty acid oxidation and promotes glycolysis, leading to cell death and fibrosis. Mechanistically, we revealed that PP2Acα dephosphorylates ACC through interaction with B56δ, leading to the regulation of fatty acid oxidation. Furthermore, PP2Acα also dephosphorylates p-Glut1 (Thr478) and suppresses Trim21-mediated Glut1 ubiquitination and degradation, leading to the promotion of glucose intake and glycolysis. Thus, this study adds new insight into the tubular cell metabolic alterations in kidney diseases. PP2Acα may be a promising therapeutic target for kidney injury.

Resveratrol ameliorates high-phosphate-induced VSMCs to osteoblast-like cells transdifferentiation and arterial medial calcification in CKD through regulating Wnt/ß-catenin signaling.

Vascular smooth muscle cells (VSMCs) to osteoblast-like cells transdifferentiation induced by high-phosphate is a crucial step in the development of arterial medial calcification (AMC) in patients with chronic kidney disease (CKD), and previous studies implicate Wnt/ß-catenin signaling in osteogenic transdifferentiation of VSMCs and AMC. Given that resveratrol's ability to modulate Wnt/ß-catenin signaling in other types of cell, we tested the effect of resveratrol on high-phosphate-induced osteogenic transdifferentiation of VSMCs and AMC in CKD. Resveratrol ameliorated AMC in rats with chronic renal failure and calcium deposition in aortic rings and VSMCs cultured in a high-phosphate environment. Resveratrol also diminished high-phosphate-induced osteogenic transdifferentiation of VSMCs in cultured aortic rings and VSMCs. In vitro, resveratrol attenuated the activation of ß-catenin induced by high-phosphate and inhibited the expression of Runx2, a downstream effector of Wnt/ß-catenin signaling during osteogenic transdifferentiation of VSMCs. Intriguingly, resveratrol inhibited high-phosphate-induced phosphorylation of LRP6 (Ser1490), but didn't inhibit Wnt3a-induced phosphorylation of LRP6 (Ser1490) and Runx2 expression. The expression of several Wnts was induced by high-phosphate, but the expression of Wnt7a, not Wnt2b and Wnt10a could be suppressed by resveratrol. In addition, the expression of both porcupine and wntless, two obligatory proteins for Wnt secretion, was induced by high-phosphate in cultured aortic rings and VSMCs, which could be suppressed by resveratrol. In summary, these findings suggest that resveratrol possesses a vascular protective effect on retarding high-phosphate-induced osteogenic transdifferentiation of VSMCs and AMC in CKD by targeting Wnt/ß-catenin signaling, which may, to a large extent, via impeding Wnt secretion.

Targeting Ferroptosis Attenuates Interstitial Inflammation and Kidney Fibrosis.

BACKGROUND: Ferroptosis, an iron-dependent form of regulated necrosis mediated by lipid peroxidation, predominantly polyunsaturated fatty acids, is involved in postischemic and toxic kidney injury. However, the role and mechanisms for tubular epithelial cell (TEC) ferroptosis in kidney fibrosis remain largely unknown. OBJECTIVES: The aim of the study was to decipher the role and mechanisms for TEC ferroptosis in kidney fibrosis. METHODS: Mouse models with unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI) were generated. RESULTS: We found that TEC ferroptosis exhibited as reduced glutathione peroxidase 4 (GPX4) expression and increased 4-hydroxynonenal abundance was appeared in kidneys from chronic kidney disease (CKD) patients and mouse models with UUO or IRI. Inhibition of ferroptosis could largely mitigate kidney injury, interstitial fibrosis, and inflammatory cell accumulation in mice after UUO or IRI. Additionally, treatment of TECs with (1S,3R)-RSL-3, an inhibitor of GPX4, could enhance cell ferroptosis and recruit macrophages. Furthermore, inhibiting TEC ferroptosis reduced monocyte chemotactic protein 1 (MCP-1) secretion and macrophage chemotaxis. CONCLUSIONS: This study uncovers that TEC ferroptosis may promote interstitial fibrosis and inflammation, and targeting ferroptosis may shine a light on protecting against kidney fibrosis in patients with CKDs.

PP2A Catalytic Subunit α promotes fibroblast activation and kidney fibrosis via ERK pathway.

Protein Phosphatase 2A (PP2A), a main serine/threonine phosphatase, plays a profibrotic role in the development of different organs. However, the role and mechanisms of PP2Acα in fibroblast activation and kidney fibrosis are not fully known. Here we found that PP2Acα expression was upregulated in kidney tissue of chronic kidney disease (CKD) patients and unilateral ureter obstructive (UUO) mice. Ablation of fibroblast PP2Acα alleviates fibroblast activation and kidney fibrosis in mouse kidneys with UUO nephropathy compared with the control littermates. In primary cultured fibroblasts, PP2Acα deletion restrains TGFß1-induced fibroblast activation, which is accompanied by increased phosphorylation of the extracellular regulated kinase (ERK). Blocking ERK pathway activation by PD98059 could promote fibroblast activation, indicating that PP2Acα promotes TGFß1-induced fibroblast activation via suppressing ERK pathway. Consistently, in vivo, the activation of ERK pathway was upregulated by PP2Acα ablation in kidney fibroblasts. Together, these data uncover that PP2Acα may promote fibroblast activation and kidney fibrosis via suppressing ERK pathway, suggesting that targeting PP2Acα may provide a therapeutic effect for CKD.

Integrin ß3 Induction Promotes Tubular Cell Senescence and Kidney Fibrosis.

Tubular cell senescence is a common biologic process and contributes to the progression of chronic kidney disease (CKD); however, the molecular mechanisms regulating tubular cell senescence are poorly understood. Here, we report that integrin ß3 (ITGB3) expression was increased in tubular cells and positively correlated with fibrosis degree in CKD patients. ITGB3 overexpression could induce p53 pathway activation and the secretion of TGF-ß, which, in turn, resulted in senescent and profibrotic phenotype change in cultured tubular cells. Moreover, according to the CMAP database, we identified isoliquiritigenin (ISL) as an agent to inhibit ITGB3. ISL treatment could suppress Itgb3 expression, attenuate cellular senescence, and prevent renal fibrosis in mice. These results reveal a crucial role for integrin signaling in cellular senescence, potentially identifying a new therapeutic direction for kidney fibrosis.

Complement factor B in high glucose-induced podocyte injury and diabetic kidney disease.

The role and mechanisms for upregulating complement factor B (CFB) expression in podocyte dysfunction in diabetic kidney disease (DKD) are not fully understood. Here, analyzing Gene Expression Omnibus GSE30528 data, we identified genes enriched in mTORC1 signaling, CFB, and complement alternative pathways in podocytes from patients with DKD. In mouse models, podocyte mTOR complex 1 (mTORC1) signaling activation was induced, while blockade of mTORC1 signaling reduced CFB upregulation, alternative complement pathway activation, and podocyte injury in the glomeruli. Knocking down CFB remarkably alleviated alternative complement pathway activation and DKD in diabetic mice. In cultured podocytes, high glucose treatment activated mTORC1 signaling, stimulated STAT1 phosphorylation, and upregulated CFB expression, while blockade of mTORC1 or STAT1 signaling abolished high glucose-upregulated CFB expression. Additionally, high glucose levels downregulated protein phosphatase 2Acα (PP2Acα) expression, while PP2Acα deficiency enhanced high glucose-induced mTORC1/STAT1 activation, CFB induction, and podocyte injury. Taken together, these findings uncover a mechanism by which CFB mediates podocyte injury in DKD.

Pyruvate kinase M2 mediates fibroblast proliferation to promote tubular epithelial cell survival in acute kidney injury.

Acute kidney injury (AKI) is a devastating condition with high morbidity and mortality rates. The pathological features of AKI are tubular injury, infiltration of inflammatory cells, and impaired vascular integrity. Pyruvate kinase is the final rate-limiting enzyme in the glycolysis pathway. We previously showed that pyruvate kinase M2 (PKM2) plays an important role in regulating the glycolytic reprogramming of fibroblasts in renal interstitial fibrosis. The present study aimed to determine the role of PKM2 in fibroblast activation during the pathogenesis of AKI. We found increased numbers of S100A4 positive cells expressing PKM2 in renal tissues from mice with AKI induced via folic acid or ischemia/reperfusion (I/R). The loss of PKM2 in fibroblasts impaired fibroblast proliferation and promoted tubular epithelial cell death including apoptosis, necroptosis, and ferroptosis. Mechanistically, fibroblasts produced less hepatocyte growth factor (HGF) in response to a loss of PKM2. Moreover, in two AKI mouse models, fibroblast-specific deletion of PKM2 blocked HGF signal activation and aggravated AKI after it was induced in mice via ischemia or folic acid. Fibroblast proliferation mediated by PKM2 elicits pro-survival signals that repress tubular cell death and may help to prevent AKI progression. Fibroblast activation mediated by PKM2 in AKI suggests that targeting PKM2 expression could be a novel strategy for treating AKI.

PP2Acα promotes macrophage accumulation and activation to exacerbate tubular cell death and kidney fibrosis through activating Rap1 and TNFα production.

Macrophage accumulation and activation play an essential role in kidney fibrosis; however, the underlying mechanisms remain to be explored. By analyzing the kidney tissues from patients and animal models with kidney fibrosis, we found a large induction of PP2Acα in macrophages. We then generated a mouse model with inducible macrophage ablation of PP2Acα. The knockouts developed less renal fibrosis, macrophage accumulation, or tubular cell death after unilateral ureter obstruction or ischemic reperfusion injury compared to control littermates. In cultured macrophages, PP2Acα deficiency resulted in decreased cell motility by inhibiting Rap1 activity. Moreover, co-culture of PP2Acα-/- macrophages with tubular cells resulted in less tubular cell death attributed to downregulated Stat6-mediated tumor necrosis factor α (TNFα) production in macrophages. Together, this study demonstrates that PP2Acα promotes macrophage accumulation and activation, hence accelerates tubular cell death and kidney fibrosis through regulating Rap1 activation and TNFα production.

Tuberous sclerosis 1 (Tsc1) mediated mTORC1 activation promotes glycolysis in tubular epithelial cells in kidney fibrosis.

Energy reprogramming to glycolysis is closely associated with the development of chronic kidney disease. As an important negative regulatory factor of the mammalian target of rapamycin complex 1 (mTORC1) signal, tuberous sclerosis complex 1 (Tsc1) is also a key regulatory point of glycolysis. Here, we investigated whether Tsc1 could mediate the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells. We induced mTORC1 signal activation in tubular epithelial cells in kidneys with fibrosis via unilateral ureteral occlusion. This resulted in increased tubular epithelial cell proliferation and glycolytic enzyme upregulation. Prior incubation with rapamycin inhibited mTORC1 activation and abolished the enhanced glycolysis and tubular epithelial cell proliferation. Furthermore, knockdown of Tsc1 expression promoted glycolysis in the rat kidney epithelial cell line NRK-52E. Specific deletion of Tsc1 in the proximal tubules of mice resulted in enlarged kidneys characterized by a high proportion of proliferative tubular epithelial cells, dilated tubules with cyst formation, and a large area of interstitial fibrosis in conjunction with elevated glycolysis. Treatment of the mice with the glycolysis inhibitor 2-deoxyglucose notably ameliorated tubular epithelial cell proliferation, cystogenesis, and kidney fibrosis. Thus, our findings suggest that Tsc1-associated mTORC1 signaling mediates the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells.

FGF/FGFR2 Protects against Tubular Cell Death and Acute Kidney Injury Involving Erk1/2 Signaling Activation.

BACKGROUND: Fibroblast growth factors (FGFs) are heparin-binding proteins involved in a variety of biological processes, and part of them may act through binding with cell membrane receptor FGFR2. OBJECTIVES: To clarify the role and mechanisms of FGFR2 signaling in tubular cell survival and acute kidney injury (AKI). METHOD: In this study, kidney ischemia/reperfusion (IR) or cisplatin injection was used to induce AKI in mice. RESULTS: In the kidneys after IR or cisplatin injection, the expression of FGFs and Erk1/2 phosphorylation were elevated. To investigate the role of FGFs in tubular cell survival and AKI, a mouse model with tubular cell specific FGFR2 gene disruption was generated. The knockouts were born normal. At 2 months of age, about one-third of the knockouts developed mild hydronephrosis. Ablation of FGFR2 in tubular cells aggravated acute kidney dysfunction as well as tubular cell apoptosis induced by IR or cisplatin. In addition, Erk1/2 phosphorylation was less in the knockout kidneys than in control littermates at day 1 after cisplatin injection. In cultured NRK-52E cells, recombinant FGF2 protein induced Erk1/2 phosphorylation and inhibited cisplatin-induced cell death. PD98059 abolished Erk1/2 phosphorylation and partly reversed the protective effect of FGF2 on cisplatin-induced cell death. CONCLUSIONS: This study indicates that FGF/FGFR2 signaling plays an important role in protecting against tubular cell death and AKI, which is partly through stimulating Erk1/2 activation.

Loss of Rictor in tubular cells exaggerates lipopolysaccharide induced renal inflammation and acute kidney injury via Yap/Taz-NF-κB axis.

Our previous study demonstrated that the mammalian target of rapamycin complex 2 (mTORC2) signaling alleviates renal inflammation and protects against cisplatin-induced AKI. However, the underlying mechanisms for mTORC2 in regulating renal inflammation in AKI remain to be determined. In this study, we found that lipopolysaccharide (LPS) could activate mTORC2 signaling in NRK-52E cells, and blockage of mTORC2 signaling led to Yap/Taz degradation, which in turn activated NF-κB signaling and induced inflammatory cytokines secretion. Overexpression of constitutively active Taz (Taz-S89A) could attenuate the inflammation-amplified role of mTORC2 blockage. In mouse models, tubule-specific deletion of Rictor had higher blood urea nitrogen level, severe morphological injury as well as more inflammatory cells accumulation compared with those in their littermate controls. Overall, these results demonstrate that mTORC2 signaling protects against renal inflammation and dictates the outcome of AKI by modulating Yap/Taz degradation.

Rheb1 protects against cisplatin-induced tubular cell death and acute kidney injury via maintaining mitochondrial homeostasis.

Ras homolog enriched in brain (Rheb1), a small GTPase, plays a crucial role in regulating cell growth, differentiation, and survival. However, the role and mechanisms for Rheb1 in tubular cell survival and acute kidney injury (AKI) remain unexplored. Here we found that Rheb1 signaling was activated in kidney tubule of AKI patients and cisplatin-treated mice. A mouse model of tubule-specific deletion of Rheb1 (Tubule-Rheb1-/-) was generated. Compared to control littermates, Tubule-Rheb1-/- mice were phenotypically normal within 2 months after birth but developed more severe kidney dysfunction, tubular cell death including apoptosis, necroptosis and ferroptosis, mitochondrial defect and less PGC-1α expression after cisplatin injection. In primary cultured tubular cells, Rheb1 ablation exacerbated cisplatin-induced cell death and mitochondrial defect. Furthermore, haploinsufficiency for Tsc1 in tubular cells led to Rheb1 activation and mitigated cisplatin-induced cell death, mitochondrial defect and AKI. Together, this study uncovers that Rheb1 may protect against cisplatin-induced tubular cell death and AKI through maintaining mitochondrial homeostasis.