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IL-6/IL-6R axis plays a critical role in acute kidney injury.

ABSTRACT: The response to tissue injury involves the coordination of inflammatory and repair processes. IL-6 expression correlates with the onset and severity of acute kidney injury (AKI), but its contribution to pathogenesis remains unclear. This study established a critical role for IL-6 in both the inflammatory response and the resolution of AKI. IL-6-deficient mice were resistant to HgCl2-induced AKI compared with wild-type mice. The accumulation of peritubular neutrophils was lower in IL-6-deficient mice than in wild-type mice, and neutrophil depletion before HgCl2 administration in wild-type mice significantly reduced AKI; these results demonstrate the critical role of IL-6 signaling in the injurious inflammatory process in AKI. Renal IL-6 expression and STAT3 activation in renal tubular epithelial cells significantly increased during the development of injury, suggesting active IL-6 signaling. Although a lack of renal IL-6 receptors (IL-6R) precludes the activation of classical signaling pathways, IL-6 can stimulate target cells together with a soluble form of the IL-6R (sIL-6R) in a process termed trans-signaling. During injury,serum sIL-6R levels increased three-fold, suggesting a possible role for IL-6 trans-signaling in AKI. Stimulation of IL-6 trans-signaling with an IL-6/sIL-6R fusion protein activated STAT3 in renal tubular epithelium and prevented AKI. IL-6/sIL-6R reduced lipid peroxidation after injury, suggesting that its protective effect may be largely mediated through amelioration of oxidative stress. In summary, IL-6 simultaneously promotes an injurious inflammatory response and, through a mechanism of trans-signaling, protects the kidney from further injury.

SUBMITTER: Nechemia-Arbely Y

PROVIDER: S-EPMC2396933 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Phosphoinositide 3 Kinase γ Plays a Critical Role in Acute Kidney Injury.

Project description:Inflammatory cells contribute to the pathogenesis of renal ischemia-reperfusion injury (IRI). However, the signaling mechanisms underlying the infiltration of inflammatory cells into the kidney are not well understood. In this study, we examined the effects of phosphoinositide 3 kinase γ (PI3Kγ) on inflammatory cells infiltration into the kidney in response to ischemia-reperfusion injury. Compared with wild-type mice, PI3Kγ knockout mice displayed less IRI in the kidney with fewer tubular apoptotic cell. Furthermore, PI3Kγ deficiency decreased the number of infiltrated neutrophils, macrophages, and T cells in the kidney, which was accompanied by a decrease in the expression of pro-inflammatory cytokines in the kidney. Moreover, wild-type mice treated with AS-605240, a selective PI3Kγ inhibitor, displayed less tubular damage, accumulated fewer inflammatory cells, and expressed less proinflammatory molecules in the kidney following IRI. These results demonstrate that PI3Kγ has a critical role in the pathogenesis of kidney damage in IRI, indicating that PI3Kγ inhibition may serve as a potential therapeutic strategy for the prevention of ischemia-reperfusion-induced kidney injury.

| S-EPMC8909888 | biostudies-literature

Renal proximal tubular NEMO plays a critical role in ischemic acute kidney injury.

Project description:We determined that renal proximal tubular (PT) NF-κB essential modulator (NEMO) plays a direct and critical role in ischemic acute kidney injury (AKI) using mice lacking renal PT NEMO and by targeted renal PT NEMO inhibition with mesoscale nanoparticle-encapsulated NEMO binding peptide (NBP MNP). We subjected renal PT NEMO-deficient mice, WT mice, and C57BL/6 mice to sham surgery or 30 minutes of renal ischemia and reperfusion (IR). C57BL/6 mice received NBP MNP or empty MNP before renal IR injury. Mice treated with NBP MNP and mice deficient in renal PT NEMO were protected against ischemic AKI, having decreased renal tubular necrosis, inflammation, and apoptosis compared with control MNP-treated or WT mice, respectively. Recombinant peptidylarginine deiminase type 4 (rPAD4) targeted kidney PT NEMO to exacerbate ischemic AKI in that exogenous rPAD4 exacerbated renal IR injury in WT mice but not in renal PT NEMO-deficient mice. Furthermore, rPAD4 upregulated proinflammatory cytokine mRNA and NF-κB activation in freshly isolated renal proximal tubules from WT mice but not from PT NEMO-deficient mice. Taken together, our studies suggest that renal PT NEMO plays a critical role in ischemic AKI by promoting renal tubular inflammation, apoptosis, and necrosis.

| S-EPMC7566738 | biostudies-literature

Nrf2 Plays a Protective Role Against Intravascular Hemolysis-Mediated Acute Kidney Injury.

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| S-EPMC6619398 | biostudies-literature

mTOR plays a critical role in p53-induced oxidative kidney cell injury in HIVAN.

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| S-EPMC3742868 | biostudies-literature

Kidney VISTA prevents IFN-γ/IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury.

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| S-EPMC8718152 | biostudies-literature

lncRNA SNHG14 Plays a Role in Sepsis-Induced Acute Kidney Injury by Regulating miR-93.

Project description:Acute kidney injury (AKI) is a common organ injury in sepsis, which leads to poor prognosis. Long noncoding RNA (lncRNA) small nucleolus RNA host gene 14 (SNHG14) was recognized to induce cell injury in LPS-induced acute lung injury and Parkinson's disease. We want to investigate the functions and mechanisms of SNHG14 in sepsis-induced AKI. Increased expression of SNHG14 was observed in LPS-induced HK-2 cells, and this was due to the activation of the TLR4/NF-κB pathway. In vitro studies showed that SNHG14 was involved in the oxidative stress, inflammation, and apoptosis of LPS-induced HK-2 cells. Further investigations confirmed that SNHG14 exerted the functions via miR-93 which could regulate the activation of NF-κB and STAT3 signaling by targeting IRAK4 and IL-6R. We also found that silencing SNHG14 also alleviated cellular injury processes of IL-1β and IL-6 in HK-2 cells via miR-93. We demonstrate that SNHG14 accelerates cellular injury in sepsis-induced AKI by activating IRAK4/NF-κB and IL-6R/STAT3 signaling via miR-93.

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Curcumin plays a protective role against septic acute kidney injury by regulating the TLR9 signaling pathway.

Project description:BackgroundThis study aims to evaluate the inhibitory effect of curcumin (Cur) on the progression of septic acute kidney injury (SAKI), in order to improve the survival rate in this patient population.MethodsAcute kidney injury (AKI) was induced by cecal ligation perforation (CLP) in Sprague-Dawley (SD) rats. Using this AKI animal model, the survival rate of the rats was evaluated at different time points after Cur treatment to explore whether Cur can improve survival in an animal model of AKI. The expression levels of inflammatory factors (NF-κB, TNF-α, and IL-10), organ injury markers [urea nitrogen (UN), creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), amylase, creatine kinase (CK), and lactate dehydrogenase (LDH)], and disease progression markers [neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and cystatin-C (CysC)] were determined using an enzyme-linked immunosorbent assay (ELISA).ResultsThe serum levels of UN, Cr, NF-κB, ALT, AST, amylase, CK, LDH, inflammatory factors TNF-α and IL-10, and markers of early diagnosis of SAKI (NGAL, CysC, KIM-1) were significantly lower in the curcumin group than those in the placebo group (P<0.05). In addition, serum levels of TLR9 and its downstream molecules MyD88, IRF5, and IRF7 in the curcumin group were significantly lower than those in the placebo group (P<0.05). The application of TLR9-specific inhibitors to experimental rats led to similar results as those obtained in the curcumin group, whose detection indexes were significantly lower than those in the placebo treatment group (P<0.05).ConclusionsGiven the excellent performance of Cur in anti-tumor, anti-oxidation, anti-inflammatory, and other clinical trials, it is very likely to be further developed as a potential drug for the clinical treatment of AKI.

| S-EPMC8185681 | biostudies-literature

IL-23, but not IL-12, plays a critical role in inflammation-mediated bone disorders.

Project description:Interleukin-12 (IL-12) and IL-23 are thought to have central roles in inflammation and are critical to pathologies associated with inflammation-induced bone disorders. The deletion of IL-12p40 (a common subunit of IL-12 and IL-23) can improve bone regeneration. However, the relative roles of IL-12 and IL-23 in bone disorders are largely unknown. Methods: Ectopic bone formation and skull defect models were established to evaluate the relative roles of IL-12 and IL-23 in inflammatory bone disorders. Differences in bone mass among WT, IL-12p35-/-, and IL-12p40-/- mice (young and elderly) were detected by micro-CT. Osteogenic and osteoclastic activities were explored using ELISA, qRT-PCR, and histological analysis. Moreover, the mechanisms by which IL-12 and IL-23 regulated the differentiation of BMMSCs and RAW264.7 cells were explored using Alizarin Red and tartrate-resistant acid phosphatase staining in vitro. Apilimod was used to inhibit IL-12 and IL-23 production in vivo. Results: Mice deficient in IL-12p40 promoted bone formation and protected against aging-related bone loss. By contrast, bone loss was aggravated in IL-12-/- mice, suggesting that IL-23 may play a dominant role in inflammation-related bone disorders. Mechanistically, IL-12 and IL-23 coupled osteogenesis and osteoclastic activities to regulate bone homeostasis and repair. IL-23 deficiency increased bone formation and inhibited bone resorption. Finally, apilimod treatment significantly improved bone regeneration and calvarial defect repair. Conclusion: These data collectively uncover a previously unrecognized role of IL-23 in skeletal tissue engineering. Thus, IL-23 can act as a biomarker to predict diseases and treatment efficacy, and apilimod can be used as an effective therapeutic drug to combat inflammatory bone disorders.

| S-EPMC7086346 | biostudies-literature

The CXCL12/CXCR4 Axis Plays a Critical Role in Coronary Artery Development.

Project description:The chemokine CXCL12 and its receptor CXCR4 have many functions during embryonic and post-natal life. We used murine models to investigate the role of CXCL12/CXCR4 signaling in cardiac development and found that embryonic Cxcl12-null hearts lacked intra-ventricular coronary arteries (CAs) and exhibited absent or misplaced CA stems. We traced the origin of this phenotype to defects in the early stages of CA stem formation. CA stems derive from the peritruncal plexus, an encircling capillary network that invades the wall of the developing aorta. We showed that CXCL12 is present at high levels in the outflow tract, while peritruncal endothelial cells (ECs) express CXCR4. In the absence of CXCL12, ECs were abnormally localized and impaired in their ability to anastomose with the aortic lumen. We propose that CXCL12 is required for connection of peritruncal plexus ECs to the aortic endothelium and thus plays a vital role in CA formation.

| S-EPMC4448146 | biostudies-literature

IL-20 in Acute Kidney Injury: Role in Pathogenesis and Potential as a Therapeutic Target.

Project description:Acute kidney injury (AKI) causes over 1 million deaths worldwide every year. AKI is now recognized as a major risk factor in the development and progression of chronic kidney disease (CKD). Diabetes is the main cause of CKD as well. Renal fibrosis and inflammation are hallmarks in kidney diseases. Various cytokines contribute to the progression of renal diseases; thus, many drugs that specifically block cytokine function are designed for disease amelioration. Numerous studies showed IL-20 functions as a pro-inflammatory mediator to regulate cytokine expression in several inflammation-mediated diseases. In this review, we will outline the effects of pro-inflammatory cytokines in the pathogenesis of AKI and CKD. We also discuss the role of IL-20 in kidney diseases and provide a potential therapeutic approach of IL-20 blockade for treating renal diseases.

| S-EPMC7037658 | biostudies-literature

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