Dataset Information

Pharmacologic Blockade of ?v?1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo.

ABSTRACT: Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells in vivo is poorly understood. PDGF receptor ? (PDGFR?) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFR? promoter-driven Cre system to delete ?v integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFR?-Cre line to isolate and study renal fibroblasts ex vivo We found that renal fibroblasts express three ?v integrins, namely ?v?1, ?v?3, and ?v?5. Blockade of ?v?1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-?1 and prevented activation of the latent TGF-? complex. Continuous administration of a recently described potent small molecule inhibitor of ?v?1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of ?v?1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.

SUBMITTER: Chang Y

PROVIDER: S-EPMC5491273 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Pharmacologic Blockade of αvβ1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo.

Chang Yongen Y Lau Wei Ling WL Jo Hyunil H Tsujino Kazuyuki K Gewin Leslie L Reed Nilgun Isik NI Atakilit Amha A Nunes Ane Claudia Fernandes ACF DeGrado William F WF Sheppard Dean D

Journal of the American Society of Nephrology : JASN 20170220 7

Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells in vivo is poorly understood. PDGF receptor β (PDGFRβ) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFRβ promoter-driven Cre system to delete αv integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the ...[more]

PMID: 28220032

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Project description:Dysregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the pathogenesis of many cancers. However, the role of EZH2 in peritoneal fibrosis remains unknown. We investigated EZH2 expression in peritoneal dialysis (PD) patients and assessed its role in peritoneal fibrosis in cultured human peritoneal mesothelial cells (HPMCs) and murine models of peritoneal fibrosis induced by chlorhexidine gluconate (CG) or high glucose peritoneal dialysis fluid (PDF) by using 3-deazaneplanocin A (3-DZNeP), and EZH2 conditional knockout mice. An abundance of EZH2 was detected in the peritoneum of patients with PD associated peritonitis and the dialysis effluent of long-term PD patients, which was positively correlated with expression of TGF-β1, vascular endothelial growth factor, and IL-6. EZH2 was found highly expressed in the peritoneum of mice following injury by CG or PDF. In both mouse models, treatment with 3-DZNeP attenuated peritoneal fibrosis and inhibited activation of several profibrotic signaling pathways, including TGF-β1/Smad3, Notch1, epidermal growth factor receptor and Src. EZH2 inhibition also inhibited STAT3 and nuclear factor-κB phosphorylation, and reduced lymphocyte and macrophage infiltration and angiogenesis in the injured peritoneum. 3-DZNeP effectively improved high glucose PDF-associated peritoneal dysfunction by decreasing the dialysate-to-plasma ratio of blood urea nitrogen and increasing the ratio of dialysate glucose at 2 h after PDF injection to initial dialysate glucose. Moreover, delayed administration of 3-DZNeP inhibited peritoneal fibrosis progression, reversed established peritoneal fibrosis and reduced expression of tissue inhibitor of metalloproteinase 2, and matrix metalloproteinase-2 and -9. Finally, EZH2-KO mice exhibited less peritoneal fibrosis than EZH2-WT mice. In HPMCs, treatment with EZH2 siRNA or 3-DZNeP suppressed TGF-β1-induced upregulation of α-SMA and Collagen I and preserved E-cadherin. These results indicate that EZH2 is a key epigenetic regulator that promotes peritoneal fibrosis. Targeting EZH2 may have the potential to prevent and treat peritoneal fibrosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dataset Information

Pharmacologic Blockade of ?v?1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo.

Publications

Pharmacologic Blockade of <i>α</i>v<i>β</i>1 Integrin Ameliorates Renal Failure and Fibrosis <i>In Vivo</i>.

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