Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor

Sakai, Norihiko; Chun, Jerold; Duffield, Jeremy S.; Lagares, David; Wada, Takashi; Luster, Andrew D.; Tager, Andrew M.

doi:10.1016/j.kint.2016.09.030

Cited by 62 publications

(50 citation statements)

References 51 publications

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“…The lifespan of Mkl1/Mkl2 dKO mice was over 10 weeks, slightly longer than Srf KO mice. Previous studies showed an injury-promoting role of SRF/MKL in kidney disease [25][26][27][28] ; in contrast, data here support SRF and MKL1/MKL2 in the maintenance of normal podocyte structure and function.…”

Section: Significance Statementcontrasting

confidence: 57%

Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

Guo

Lyu

Slivano

et al. 2017

JASN

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Podocytes contain an intricate actin cytoskeleton that is essential for the specialized function of this cell type in renal filtration. Serum response factor (SRF) is a master transcription factor for the actin cytoskeleton, but the expression and function of SRF in podocytes are unknown. We found that SRF protein colocalizes with podocyte markers in human and mouse kidneys. Compared with littermate controls, mice in which the gene was conditionally inactivated with - exhibited early postnatal proteinuria, hypoalbuminemia, and azotemia. Histologic changes in the mutant mice included glomerular capillary dilation and mild glomerulosclerosis, with reduced expression of multiple canonical podocyte markers. We also noted tubular dilation, cell proliferation, and protein casts as well as reactive changes in mesangial cells and interstitial inflammation. Ultrastructure analysis disclosed foot process effacement with loss of slit diaphragms. To ascertain the importance of SRF cofactors in podocyte function, we disabled the myocardin-related transcription factor A and B genes. Although loss of either SRF cofactor alone had no observable effect in the kidney, deficiency of both recapitulated the -null phenotype. These results establish a vital role for SRF and two SRF cofactors in the maintenance of podocyte structure and function.

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Section: Significance Statementcontrasting

confidence: 57%

Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

Guo

Lyu

Slivano

et al. 2017

JASN

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“…The pro-healing activity of LPA is attributed to a combined effect on fibroblast proliferation and migration and to chemotactic activity toward macrophages; these are key events in wound healing [19]. LPA-LPAR1 signaling directly drives connective tissue growth factor (CTGF) expression after injury and induces the proliferation of primary proximal tubular epithelial cells [22] and primary mesothelial cells [23]. In our study, we showed that the concentration of LPA in CSF was positively correlated with LF thickness.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

Zhou

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hypertrophic ligamentum flavum (LF) is a major cause of lumbar spinal stenosis. Our previous work showed that high levels of lysophosphatidic acid (LPA) expression are positively correlated with LF hypertrophy. This study aimed to further unveil how LPA regulates LF hypertrophy Methods: We studied LPAR1 expression in human LF cells using PCR and western blotting. Cell viability cell cycle, apoptosis rate and molecular mechanisms were assayed in LPAR1 knockdown or overexpression LF cells. LF hypertrophy and the molecular mechanism was confirmed in human samples and in in vivo studies. Results: The expression of LPA and its receptor LPAR1 is significantly higher in tissues or cells harvested from hypertrophic LF compared to healthy controls. Moreover, LPA promoted LF cell proliferation by interacting with LPAR1. This conclusion is supported by the fact that depletion or overexpression of LPAR1 changed the effect of LPA on LF cell proliferation. LPA also inhibits apoptosis in LF cells through the receptor LPAR1. Importantly, we demonstrated that the LPA-LPAR1 interaction initiated Akt phosphorylation and determined cell proliferation and apoptosis. Our in vitro findings were supported by our in vivo evidence that lyophilized LPA significantly induced LF hypertrophy via the LPAR1-Akt signaling pathway. More importantly, targeted inhibition of LPAR1 by Ki16425 with a gel sponge implant effectively reduced LPA-associated LF hypertrophy. Taken together, these data indicate that LPA binds to the receptor LPAR1 to induce LF cell proliferation and inhibit apoptosis by activating AKT signaling cascades. Targeting this signaling cascade with Ki16425 is a potential therapeutic strategy for preventing LF hypertrophy. Conclusion: LPA-LPAR1-Akt activation is positively correlated with the proliferation and survival of LF cells. LPAR1 could be a target for new drugs and the development of new therapeutic methods for treating LF hypertrophy.

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“…Moreover, when the LPA 1 receptor was blocked, profibrotic cytokines (connective tissue growth factor and transforming growth factor-β) are significantly down-regulated [114]. In one study, it was confirmed that LPA-LPA 1 signaling directly induces connective tissue growth factor (CTGF) expression in primary proximal tubular epithelial cells via the myocardin-related transcription factor-serum response factor pathway [116]. It was worth noting that the glomerular LPA1 receptor does not participate in the role of TIF caused by UUO [114].…”

Section: Lpar and Renal Fibrosismentioning

confidence: 95%

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

Xiang¹,

Lü²,

Shao³

et al. 2020

J. Cancer

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Lysophosphatidic acid (LPA, 1-acyl-2-hemolytic-sn-glycerol-3-phosphate) extracted from membrane phospholipid is a kind of simple bioactive glycophospholipid, which has many biological functions such as stimulating cell multiplication, cytoskeleton recombination, cell survival, drug-fast, synthesis of DNA and ion transport. Current studies have shown that six G-coupled protein receptors (LPAR1-6) can be activated by LPA. They stimulate a variety of signal transduction pathways through heterotrimeric G-proteins (such as Gα12/13, Gαq/11, Gαi/o and GαS). LPA and its receptors play vital roles in cancers, nervous system diseases, cardiovascular diseases, liver diseases, metabolic diseases, etc. In this article, we discussed the structure of LPA receptors and elucidated their functions in various diseases, in order to better understand them and point out new therapeutic schemes for them.

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Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor

Cited by 62 publications

References 51 publications

Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

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