Connective tissue growth factor regulates fibrosis-associated renal lymphangiogenesis

Kinashi, Hiroshi; Falke, Lucas L.; Nguyen, Tri Q.; Bovenschen, Niels; Aten, Jan; Leask, Andrew; Ito, Yasuhiko; Goldschmeding, Roel

doi:10.1016/j.kint.2017.03.029

Cited by 69 publications

(70 citation statements)

References 47 publications

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“…Both CCN2 and other matricellular proteins can bind to other receptors, including tropomyosin receptor kinase A (TrkA), integrins, and heparan sulphate proteoglycans. Additionally, CCN2 can interact with growth factors such as TGF-β and vascular endothelial growth factor, and modify their function [33][34][35][36]. In the present study, we have found that CCN2 regulates fibrosis in the kidney and EMT in cultured renal cells via EGFR.…”

Section: Introductionsupporting

confidence: 56%

“…EGFR and TrkA crosstalk has been previously described in CCN2-stimulated tubular epithelial cells [31] and monocytes [36]. Several studies have shown that K252a, an alkaloid-like kinase inhibitor known to selectively inhibit TrkA kinase activity [43], blocks CCN2(IV)-induced activation of several signalling systems, including mitogen-activated protein kinases (MAPKs), and ECM production [33,43].…”

Section: Ccn2(iv) Regulates Ecm Protein Synthesis In Cultured Renal Fmentioning

confidence: 99%

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Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation

Rayego‐Mateos

Morgado‐Pascual

Rodrigues-Díez

et al. 2018

The Journal of Pathology

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Connective tissue growth factor (CCN2/CTGF) is a matricellular protein that is overexpressed in progressive human renal diseases, mainly in fibrotic areas. In vitro studies have demonstrated that CCN2 regulates the production of extracellular matrix (ECM) proteins and epithelial-mesenchymal transition (EMT), and could therefore contribute to renal fibrosis. CCN2 blockade ameliorates experimental renal damage, including diminution of ECM accumulation. We have reported that CCN2 and its C-terminal degradation product CCN2(IV) bind to epidermal growth factor receptor (EGFR) to modulate renal inflammation. However, the receptor involved in CCN2 profibrotic actions has not been described so far. Using a murine model of systemic administration of CCN2(IV), we have unveiled a fibrotic response in the kidney that was diminished by EGFR blockade. Additionally, in conditional CCN2 knockout mice, renal fibrosis elicited by folic acid-induced renal damage was prevented, and this was linked to inhibition of EGFR pathway activation. Our in vitro studies demonstrated a direct effect of CCN2 via the EGFR pathway on ECM production by fibroblasts and the induction of EMT in tubular epithelial cells. Our studies clearly show that the EGFR regulates CCN2 fibrotic signalling in the kidney, and suggest that EGFR pathway blockade could be a potential therapeutic option to block CCN2-mediated profibrotic effects in renal diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Introductionsupporting

confidence: 56%

Section: Ccn2(iv) Regulates Ecm Protein Synthesis In Cultured Renal Fmentioning

confidence: 99%

Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation

Rayego‐Mateos

Morgado‐Pascual

Rodrigues-Díez

et al. 2018

The Journal of Pathology

Self Cite

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“…The injury tubules produce a large amount of VEGF-C and VEGF-D during acute kidney injury and chronic kidney disease [49]. Kinashi et al [50] found that connective tissue growth factor (CTGF) is another important determinant of lymphangiogenesis. The increase of LVs and VEGF-C in obstructed and ischemia-reperfusion injury kidneys was significantly reduced in CTGF knockout compared to wild-type mice.…”

Section: Lymphangiogenesis and Kidney Diseasementioning

confidence: 99%

Lymphatic Vessels Enhancing Adaptive Immunity Deteriorates Renal Inflammation and Renal Fibrosis

Pei

Zeng

et al. 2020

Kidney Dis

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Background: Lymphatic vessels transport lymph away from microvascular beds into the cardiovascular system. The basic function of the lymphatic system include absorption of wa ter and macromolecules in the interstitial fluid, which plays an important role in maintaining osmotic balance of the body. Recent studies have shown that lymphangiogenesis is associated with tumor metabolism, injury repair, and chron ic inflammation, and deteriorates disease progression via immune cell trafficking. Summary: Renal interstitial lymph angiogenesis is found in patients with chronic kidney dis ease and a series of animal models of renal fibrosis. Lymphat ic vessels transfer antigen and antigenpresenting cells from peripheral tissues to lymph nodes, which initiates adaptive immunity and in turn deteriorates renal inflammation and renal fibrosis, even in nonautoimmune renal diseases. Key Messages: This review summarizes the latest findings on how lymphatics participate in the progression of chronic kid ney disease. This discussion will serve to highlight the role of adaptive immunity in noninfectious and nonautoimmune nephropathy, in order to provide new ideas and methods for prevention and treatment of kidney diseases.

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“…VEGF‐A‐knockout mice show losses of podocyte foot processes and endothelial cell fenestrations, suggesting a crucial role for VEGF in maintaining the function of the glomerular filtration barrier (Sison et al, ). In contrast, VEGF expression correlates with fibrotic markers in diabetic kidneys (Kinashi et al, ), and a selective VEGFR‐3 inhibitor ameliorates diabetic kidney injury in db/db mice (Hwang et al, ). Thus, the protective effect of VEGF in the kidney is controversial.…”

Section: Pgc‐1α: a Key Player In Metabolismmentioning

confidence: 99%

PGC‐1α, a potential therapeutic target against kidney aging

et al. 2019

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Aging is defined as changes in an organism over time. The proportion of the aged population is markedly increasing worldwide. The kidney, as an essential organ with a high energy requirement, is one of the most susceptible organs to aging. It is involved in glucose metabolism via gluconeogenesis, glucose filtration and reabsorption, and glucose utilization. Proximal tubular epithelial cells (PTECs) depend on lipid metabolism to meet the high demand for ATP. Recent studies have shown that aging‐related kidney dysfunction is highly associated with metabolic changes in the kidney. Peroxisome proliferator‐activated receptor gamma coactivator‐1 alpha (PGC‐1α), a transcriptional coactivator, plays a major role in the regulation of mitochondrial biogenesis, peroxisomal biogenesis, and glucose and lipid metabolism. PGC‐1α is abundant in tissues, including kidney PTECs, which demand high energy. Many in vitro and in vivo studies have demonstrated that the activation of PGC‐1α by genetic or pharmacological intervention prevents telomere shortening and aging‐related changes in the skeletal muscle, heart, and brain. The activation of PGC‐1α can also prevent kidney dysfunction in various kidney diseases. Therefore, a better understanding of the effect of PGC‐1α activation in various organs on aging and kidney diseases may unveil a potential therapeutic strategy against kidney aging.

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Connective tissue growth factor regulates fibrosis-associated renal lymphangiogenesis

Cited by 69 publications

References 47 publications

Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation

Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation

Lymphatic Vessels Enhancing Adaptive Immunity Deteriorates Renal Inflammation and Renal Fibrosis

PGC‐1α, a potential therapeutic target against kidney aging

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