Proteinase-activated Receptor-2 Transactivation of Epidermal Growth Factor Receptor and Transforming Growth Factor-β Receptor Signaling Pathways Contributes to Renal Fibrosis

Chung, Hyunsoo; Ramachandran, Rithwik; Hollenberg, Morley D.; Muruve, Daniel A.

doi:10.1074/jbc.m113.492793

Cited by 83 publications

(97 citation statements)

References 49 publications

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“…Our lab has shown that in human VSMCs, PAR-1 mediated transactivation of the EGFR involves MMPs . Reports by Chung et al (Chung et al 2013) demonstrate PAR-2 transactivation of TGFBR1 in their renal fibrosis model to have identical mechanisms to that occurring in our VSMCs model ) with the exception that MMPs are involved in the phosphorylation of Smad. The phosphorylation of Smad in the carboxy terminal is a direct result of the kinase activity of TGFBR1 directed to Smad2 or Smad3 (Kamato et al 2013(Kamato et al , 2014, however Smad transcription factors are also phosphorylated in the linkage region this response is not direct but is mediated via serine/threonine kinases (Kamato et al 2013).…”

Section: Gpcr Transactivation Of Protein Serine/threonine Receptorssupporting

confidence: 74%

Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

Chaplin

Thach

Hollenberg

et al. 2017

J. Cell Commun. Signal.

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G protein coupled receptor (GPCR) signalling is mediated by transactivation independent and transactivation dependent pathways. GPCRs transactivate protein tyrosine kinase receptors (PTKRs) and protein serine/threonine kinase receptors (PS/TKR). Since the initial observations of transactivation dependent signalling, there has been an effort to understand the mechanisms behind this phenomena. GPCR signalling has evolved to include biased signalling. Biased signalling, whereby selected ligands can activate the same GPCR that can generate multiple signals, but drive only a unique response. To date, there has been no focus on the ability of biased agonists to activate the PTKR and PS/TKR transactivation pathways differentially. As such, this represents a novel direction for future research. This review will discuss the main mechanisms of GPCR mediated receptor transactivation and the pathways involved in intracellular responses.

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Section: Gpcr Transactivation Of Protein Serine/threonine Receptorssupporting

confidence: 74%

Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

Chaplin

Thach

Hollenberg

et al. 2017

J. Cell Commun. Signal.

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“…Accordingly, we hypothesize that p38 MAPK transactivates the TGF-β receptor resulting in downstream pro-fibrotic signalling. Indeed, transactivation of the TGF-β receptor by other mechanisms has been reported in cultured proximal tubule epithelial cells and vascular smooth muscle cells [48,49]. …”

Section: Discussionmentioning

confidence: 99%

Podocyte‐derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36

Munkonda

Akbari

Landry

et al. 2018

J of Extracellular Vesicle

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Tubulointerstitial fibrosis is a hallmark of advanced diabetic kidney disease that is linked to a decline in renal function, however the pathogenic mechanisms are poorly understood. Microparticles (MPs) are 100–1000 nm vesicles shed from injured cells that are implicated in intercellular signalling. Our lab recently observed the formation of MPs from podocytes and their release into urine of animal models of type 1 and 2 diabetes and in humans with type 1 diabetes. The purpose of the present study was to examine the role of podocyte MPs in tubular epithelial cell fibrotic responses. MPs were isolated from the media of differentiated, untreated human podocytes (hPODs) and administered to cultured human proximal tubule epithelial cells (PTECs). Treatment with podocyte MPs increased p38 and Smad3 phosphorylation and expression of the extracellular matrix (ECM) proteins fibronectin and collagen type IV. MP-induced responses were attenuated by co-treatment with the p38 inhibitor SB202190. A transforming growth factor beta (TGF-β) receptor inhibitor (LY2109761) blocked MP-induced Smad3 phosphorylation and ECM protein expression but not p38 phosphorylation suggesting that these responses occurred downstream of p38. Finally, blockade of the class B scavenger receptor CD36 completely abrogated MP-mediated p38 phosphorylation, downstream Smad3 activation and fibronectin/collagen type IV induction. Taken together our results suggest that podocyte MPs interact with proximal tubule cells and induce pro-fibrotic responses. Such interactions may contribute to the development of tubular fibrosis in glomerular disease.

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“…15,16,32,33 In this regard, we recently reported that in a model of accelerated diabetic nephropathy (endothelial nitric oxide synthase-streptozotocin mice), administration of the EGFR tyrosine kinase inhibitor, erlotinib, markedly reduced albuminuria and glomerulosclerosis. 20 Similarly, studies in diabetic rats reported that a different EGFR tyrosine kinase inhibitor, PKI 166, attenuated early glomerular enlargement and preserved podocytes.…”

Section: Discussionmentioning

confidence: 99%

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

Chen¹,

Chen

Harris

2015

Journal of the American Society of Nephrology

113

114

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The generation of reactive oxygen species (ROS), particularly superoxide, by damaged or dysfunctional mitochondria has been postulated to be an initiating event in the development of diabetes complications. The glomerulus is a primary site of diabetic injury, and podocyte injury is a classic hallmark of diabetic glomerular lesions. In streptozotocin-induced type 1 diabetes, podocyte-specific EGF receptor (EGFR) knockout mice (EGFR podKO ) and their wild-type (WT) littermates had similar levels of hyperglycemia and polyuria, but EGFR podKO mice had significantly less albuminuria and less podocyte loss compared with WT diabetic mice. Furthermore, EGFR podKO diabetic mice had less TGF-b1 expression, Smad2/3 phosphorylation, and glomerular fibronectin deposition. Immunoblotting of isolated glomerular lysates revealed that the upregulation of cleaved caspase 3 and downregulation of Bcl2 in WT diabetic mice were attenuated in EGFR podKO diabetic mice. Administration of the SOD mimetic mito-tempol or the NADPH oxidase inhibitor apocynin attenuated the upregulation of p-c-Src, p-EGFR, p-ERK1/2, p-Smad2/3, and TGF-b1 expression and prevented the alteration of cleaved caspase 3 and Bcl2 expression in glomeruli of WT diabetic mice. High-glucose treatment of cultured mouse podocytes induced similar alterations in the production of ROS; phosphorylation of c-Src, EGFR, and Smad2/3; and expression of TGF-b1, cleaved caspase 3, and Bcl2. These alterations were inhibited by treatment with mito-tempol or apocynin or by inhibiting EGFR expression or activity. Thus, results of our studies utilizing mice with podocyte-specific EGFR deletion demonstrate that EGFR activation has a major role in activating pathways that mediate podocyte injury and loss in diabetic nephropathy.

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Proteinase-activated Receptor-2 Transactivation of Epidermal Growth Factor Receptor and Transforming Growth Factor-β Receptor Signaling Pathways Contributes to Renal Fibrosis

Cited by 83 publications

References 49 publications

Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

Podocyte‐derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

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