Molecular pathways in peritoneal fibrosis

Balzer, Michael S.

doi:10.1016/j.cellsig.2020.109778

Cited by 63 publications

(99 citation statements)

References 125 publications

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“…[1] While our understanding of the molecular mechanisms of such PD-related structural and functional aberrations of the peritoneum has grown considerably over the last decades, successful translation of pathophysiological insights into therapeutic options for peritoneal fibrosis are scarce. [2] High glucose concentrations applied in PD create a diabetic state of the peritoneal cavity. [3] Mesothelial cells (MC) are the first cells of the peritoneal membrane that get in contact with glucose-containing PDF.…”

Section: Introductionmentioning

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

Balzer

Rong

Nordlohne

et al. 2020

Preprint

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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 PET status for glucose, urea and creatinine were analyzed. Expression of SGLT and 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 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. Pro-inflammatory 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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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

Balzer

Rong

Nordlohne

et al. 2020

Preprint

Self Cite

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“…Sustained exposure of high-glucose PD solution induces peritoneal fibrosis and triggers an increased angiogenesis. Morphologically, it is characterized by a detachment of the mesothelial layer, angiogenesis, a progressive thickening with ECM deposition, and an increased presence of myofibroblasts which were responsible for collagen production (Balzer, 2020). Peritoneal angiogenesis results in increased production of VEGF and other proangiogenic factors which stimulate the formation of new capillaries in the PM.…”

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine Ameliorates Peritoneal Angiogenesis by Regulating VEGF/Hippo/YAP Signaling

Zhu

Shan

et al. 2021

Front. Pharmacol.

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Angiogenesis of human peritoneal vascular endothelial cells (HPVECs), linked to vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling, is a complication of peritoneal fibrosis (PF). Hippo/YAP signaling interacts with VEGF/VEGFR2 signaling, but the effect on peritoneal angiogenesis and PF has not been studied. We tested VEGF/Hippo/YAP inhibition by tetramethylpyrazine (TMP) in PF mice and HPVECs. This treatment ameliorated peritoneal dialysis (PD)–induced angiogenesis and PF. In mice, PF was associated with upregulation of VEGF, and TMP ameliorated submesothelial fibrosis, perivascular bleeding, and Collagen I abundance. In HPVECs, angiogenesis occurred due to human peritoneal mesothelial cells (HPMCs)–conditioned medium, and TMP alleviated HPVECs migration, tube formation, and YAP nuclear translocation. YAP knockdown PF mouse and HPVEC models were established to further confirm our finding. YAP deletion attenuated the PD-induced or VEGF-induced increase in angiogenesis and PF. The amount of CYR61 and CTGF was significantly less in the YAP knockdown group. To study the possibility that TMP could benefit angiogenesis, we measured the HPVECs migration and tube formation and found that both were sharply increased in YAP overexpression; TMP treatment partly abolished these increases. As well, the amount of VEGFR localized in the trans-Golgi network was lower by double immunofluorescence; VEGFR and its downstream signaling pathways including p-ERK, p-P38, and p-Akt were more in HPVECs with YAP overexpression. Overall, TMP treatment ameliorated angiogenesis, PF, and peritoneum injury. These changes were accompanied by inhibition of VEGF/Hippo/YAP.

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“…The binding of TGF-β to the transmembrane TβRII initiates TβRI activation and recruitment. TβRII serine/threonine kinase phosphorylates serine and threonine residues on the transmembrane of TβRI, inducing the phosphorylation of Smad 2 and 3 serine residues [ 5 , 6 ]. The phosphorylated Smad 2 and 3 recruit Smad 4, which is translocated to the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells

Lho

Heo

et al. 2021

IJMS

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We investigated the effectiveness of the transforming growth factor beta-1 (TGF-β) receptor inhibitor GW788388 on the epithelial to mesenchymal transition (EMT) using human peritoneal mesothelial cells (HPMCs) and examined the effectiveness of GW788388 on the peritoneal membrane using a peritoneal fibrosis mouse model. HPMCs were treated with TGF-β with or without GW788388. Animal experiments were conducted on male C57/BL6 mice. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate. GW788388 was administered by once-daily oral gavage. The morphological change, cell migration, and invasion resulted from TGF-β treatment, but these changes were attenuated by cotreatment with GW788388. TGF-β-treated HPMCs decreased the level of the epithelial cell marker and increased the levels of the mesenchymal cell markers. Cotreatment with GW788388 reversed these changes. Phosphorylated Smad2 and Smad3 protein levels were stimulated with TGF-β and the change was attenuated by cotreatment with GW788388. For the peritoneal fibrosis mice, thickness and collagen deposition of parietal peritoneum was increased, but this change was attenuated by cotreatment with GW788388. GW788388, an orally available potent TGF-β receptor type 1 inhibitor, effectively attenuated TGF-β-induced EMT in HPMCs. Cotreatment with GW788388 improved peritoneal thickness and fibrosis, and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.

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Molecular pathways in peritoneal fibrosis

Cited by 63 publications

References 125 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

Tetramethylpyrazine Ameliorates Peritoneal Angiogenesis by Regulating VEGF/Hippo/YAP Signaling

Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells

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