Protein kinase C beta deficiency increases glucose-mediated peritoneal damage via M1 macrophage polarization and up-regulation of mesothelial protein kinase C alpha

Balzer, Michael S.; Helmke, Alexandra; Ackermann, Martina; Casper, Janis; Dong, Lei; Hiß, Marcus; Kiyan, Yulia; Rong, Song; Timrott, Kai; Vietinghoff, Sibylle von; Wang, Le; Haller, Hermann; Shushakova, Nelli

doi:10.1093/ndt/gfy282

Cited by 14 publications

(18 citation statements)

References 50 publications

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“…Both in murine (MPMCs) and in human peritoneal mesothelial cells (HPMCs), dapagliflozin reduced MCP-1 release in a high-glucose milieu, while it had no effect in normal glucose conditions ( Figure 6C). Consistent with our previous findings, mesothelial cells increased MCP-1 production in response to high glucose, while murine macrophages produced less, possibly reflecting a shift to M2 polarization under high-glucose conditions [13]. Similarly, dapagliflozin administered in normal glucose conditions reduced MCP-1 release but had no further effect in high-glucose conditions.…”

Section: Dapagliflozin Abrogates Proinflammatory Signaling In Murine supporting

confidence: 90%

“…Because dapagliflozin is easily soluble in aqueous solution, no vehicle was necessary. On the last day of experiments, functional analysis of the PM was performed via ultrafiltration and an equilibration test, and peritoneal effluents were sampled as previously described [4,13]. Thereafter, tissue samples were collected from the anterior abdominal wall for histological and immunofluorescence analysis.…”

Section: Peritoneal Dialysis Fluid Exposure Model In Micementioning

confidence: 99%

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SGLT2 Inhibition by Intraperitoneal Dapagliflozin Mitigates Peritoneal Fibrosis and Ultrafiltration Failure in a Mouse Model of Chronic Peritoneal Exposure to High-Glucose Dialysate

et al. 2020

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Peritoneal dialysis (PD) is limited by glucose-mediated peritoneal membrane (PM) fibrosis, angiogenesis, and ultrafiltration failure. Influencing PM integrity by pharmacologically targeting sodium-dependent glucose transporter (SGLT)-mediated glucose uptake has not been studied. In this study, wildtype C57Bl/6N mice were treated with high-glucose dialysate via an intraperitoneal catheter, with or without addition of selective SGLT2 inhibitor dapagliflozin. PM structural changes, ultrafiltration capacity, and peritoneal equilibration testing (PET) status for glucose, urea, and creatinine were analyzed. Expression of SGLT and facilitative glucose transporters (GLUT) was analyzed by real-time PCR, immunofluorescence, and immunohistochemistry. Peritoneal effluents were analyzed for cellular and cytokine composition. We found that peritoneal SGLT2 was expressed in mesothelial cells and in skeletal muscle. Dapagliflozin significantly reduced effluent transforming growth factor (TGF-β) concentrations, peritoneal thickening, and fibrosis, as well as microvessel density, resulting in improved ultrafiltration, despite the fact that it did not affect development of high-glucose transporter status. In vitro, dapagliflozin reduced monocyte chemoattractant protein-1 release under high-glucose conditions in human and murine peritoneal mesothelial cells. Proinflammatory cytokine release in macrophages was reduced only when cultured in high-glucose conditions with an additional inflammatory stimulus. In summary, dapagliflozin improved structural and functional peritoneal health in the context of high-glucose PD.

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Section: Dapagliflozin Abrogates Proinflammatory Signaling In Murine supporting

confidence: 90%

Section: Peritoneal Dialysis Fluid Exposure Model In Micementioning

confidence: 99%

SGLT2 Inhibition by Intraperitoneal Dapagliflozin Mitigates Peritoneal Fibrosis and Ultrafiltration Failure in a Mouse Model of Chronic Peritoneal Exposure to High-Glucose Dialysate

et al. 2020

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“…In the early stages, the adverse effects of high glucose on peritoneal tissue are manifested in its induced cellular oxidative damage and mitochondrial dysfunction . High glucose peritoneal dialysate induces ROS production in peritoneal MCs, which promotes macrophage polarization to aggravate peritoneal mesothelial injury . And it has been reported that hydrogen can regulate ROS activation in macrophages .…”

Section: Discussionmentioning

confidence: 99%

“…22 High glucose peritoneal dialysate induces ROS production in peritoneal MCs, which promotes macrophage polarization to aggravate peritoneal mesothelial injury. 23 And it has been reported that hydrogen can regulate ROS activation in macrophages. 24 Our research shows that molecular hydrogen significantly attenuated high glucose-induced mitochondrial membrane destruction in peritoneal MCs and reduced intracellular ROS production, consistent with the findings of studies on hydrogen effects on cerebral ischemia-reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Molecular hydrogen regulates PTEN‐AKT‐mTOR signaling via ROS to alleviate peritoneal dialysis‐related peritoneal fibrosis

Chen

Liu

et al. 2020

FASEB j.

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As a convenient, effective and economical kidney replacement therapy for end‐stage renal disease (ESRD), peritoneal dialysis is available in approximately 11% of ESRD patients worldwide. However, long‐term peritoneal dialysis treatment causes peritoneal fibrosis. In recent years, the application potential of molecular hydrogen in the biomedicine has been well recognized. Molecular hydrogen selectively scavenges cytotoxic reactive oxygen species (ROS) and acts as an antioxidant. In this experiment, a high glucose‐induced peritoneal fibrosis mouse model was successfully established by intraperitoneal injection of high glucose peritoneal dialysate, and peritoneal fibrosis mice were treated with hydrogen‐rich peritoneal dialysate. In addition, in vitro studies of high glucose‐induced peritoneal fibrosis were performed using MeT‐5A cells. In vitro and in vivo experiments show that molecular hydrogen could inhibit peritoneal fibrosis progress induced by high glucose effectively. Furthermore, it has been found that molecular hydrogen alleviate fibrosis by eliminating intracellular ROS and inhibiting the activation of the PTEN/AKT/mTOR pathway. The present data proposes that molecular hydrogen exerts the capacity of anti‐peritoneal fibrosis through the ROS/PTEN/AKT/mTOR pathway. Therefore, molecule hydrogen is a potential, safe, and effective treatment agent, with peritoneal protective property and great clinical significance.

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“…The cell lines were identified by the typical cobblestone morphology of confluent monolayers and by positive staining for E-cadherin, ZO-1, α-SMA, and pan-cytokeratin after 3-day culture at 37 °C without interferon gamma (non-permissive conditions). Primary preitoneal mouse macrophages were isolated from uPAR-/-mice as described previously36 .Raw 264.7 mouse macrophage cell line was from ATCC and cultivated as recommended by the supplier. HK-2 human kidney proximal tubule epithelial cells were from ATCC and cultivated as recommended by the supplier in Keratinocyte Serum Free Medium containing 0.05 mg/ml bovine pituitary extract and 5 ng/ml EGF.Mesothelial cells were transfected using PolyPlus transfection reagents accordingly to the manufacturer instructions.…”

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confidence: 99%

Urokinase receptor associates with TLR4 interactome to promote LPS response

Kiyan

Tkachuk

Gorrasi

et al. 2020

Preprint

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GPI-anchored uPAR is the receptor for the extracellular serine protease urokinase-type plasminogen activator (uPA). Binding of uPA to uPAR localizes proteolytic cascade activation at the cell surface and can induce intracellular signaling. As uPAR possesses no transmembrane domain, it relies on uPAR cross-talk with various membrane receptors. Though uPAR role in inflammatory processes is well documented, underlying mechanisms are not fully understood. In this study we demonstrate that uPAR is a part of Toll-like receptor 4 (TLR4) interactome. GPI-uPAR and soluble uPAR colocalized with TLR4 on the cell membrane and interacted with scavenger receptor CD36. We show that downregulation of uPAR expression resulted in diminished LPS-induced TLR4 signaling, less activation of NFκB, and decreased secretion of inflammatory mediators in myeloid and nonmyeloid cells in vitro. In vivo uPAR-/-mice demonstrated strongly diminished inflammatory response and better organ functions in cecal ligation and puncture mouse polymicrobial sepsis model. Our data show that uPAR can interfere with innate immunity response via TLR4 and this mechanism represents a potentially important target in inflammation and sepsis therapy.

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Protein kinase C beta deficiency increases glucose-mediated peritoneal damage via M1 macrophage polarization and up-regulation of mesothelial protein kinase C alpha

Abstract: PKCβ as the dominant PKC isoform in MPMΦ is up-regulated by HG PD fluid and exerts anti-inflammatory effects during PD through regulation of MPMΦ M1/M2 polarization and control of the dominant mesothelial PKC isoform α.

Cited by 14 publications

References 50 publications

SGLT2 Inhibition by Intraperitoneal Dapagliflozin Mitigates Peritoneal Fibrosis and Ultrafiltration Failure in a Mouse Model of Chronic Peritoneal Exposure to High-Glucose Dialysate

SGLT2 Inhibition by Intraperitoneal Dapagliflozin Mitigates Peritoneal Fibrosis and Ultrafiltration Failure in a Mouse Model of Chronic Peritoneal Exposure to High-Glucose Dialysate

Molecular hydrogen regulates PTEN‐AKT‐mTOR signaling via ROS to alleviate peritoneal dialysis‐related peritoneal fibrosis

Urokinase receptor associates with TLR4 interactome to promote LPS response

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