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Editorial
. 2021 Mar 1;320(3):F322-F324.
doi: 10.1152/ajprenal.00685.2020. Epub 2021 Jan 25.

Cooperative activation of divergent pathways by LPAR1 and LPAR2 receptors in fibrotic signaling

Marpadga A Reddy  1 , Rama Natarajan  1
Affiliations
Editorial

Cooperative activation of divergent pathways by LPAR1 and LPAR2 receptors in fibrotic signaling

Marpadga A Reddy et al. Am J Physiol Renal Physiol. .
No abstract available

Keywords: acute kidney injury; chronic kidney disease; fibrosis; lysophosphatidic acid; tubulointerstitial fibrosis.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Figure 1.
Figure 1.
Divergent signaling mechanisms elicited by lysophosphatidic acid (LPA) 1 receptor (LPAR)1 and LPAR2 during acute kidney injury (AKI) and ischemia-reperfusion injury and the transition into chronic kidney disease (CKD). Proximal tubular (PT) cells in the kidney cortex have high regenerative capacity and mostly recover after AKI. However, recurrent injuries can adversely affect recovery process resulting in tubular structural changes, dedifferentiation, and atrophy. Maladaptive signaling in PTs with atrophy can increase LPA levels via actions of autotaxin (ATX). Changes in the expression and activation of LPAR1 and LPAR2 stimulate divergent signaling pathways downstream of each of these two receptors, which converge at the level of activator protein (AP)-1 activation. These pathways from LPAR1 and LPAR2, along with transforming growth factor-β (TGF-β) Smad2/3 signaling activated by LPAR2, additively increase and promote persistent production of fibrotic growth factors/cytokines such as platelet-derived growth factor (PDGF) and connective tissue growth factor (CTGF), which contribute to the fibrosis associated with AKI and transition to CKD. LPA signaling during acute injury may also lead to chronic potentiation of LPA- and TGF-β-induced signaling and activity possibly due to epigenetic mechanisms. The detailed understanding of the relationships between LPA, LPAR1, and LPAR2, and TGF-β signaling in PTs can aid in the development of much-needed effective antifibrotic therapies. ECM, extracellular matrix; EGFR, epidermal growth factor receptor; ERK1/2, extracellular signal-regulated kinase 1 and 2; JNK, c-Jun NH2-terminal kinase; p, phosphorylated; LAP, latency-associated peptide; LTBP, latent TGF-β-binding protein.
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References

    1. He L, Wei Q, Liu J, Yi M, Liu Y, Liu H, Sun L, Peng Y, Liu F, Venkatachalam MA, Don Z. AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms. Kidney Int 92: 1071–1083, 2017. doi:10.1016/j.kint.2017.06.030. - DOI - PMC - PubMed
    1. Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 371: 58–66, 2014. doi:10.1056/NEJMra1214243. - DOI - PMC - PubMed
    1. Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 16: 535–543, 2010. doi:10.1038/nm.2144. - DOI - PMC - PubMed
    1. Park F, Miller DD. Role of lysophosphatidic acid and its receptors in the kidney. Physiol Genomics 49: 659–666, 2017. doi:10.1152/physiolgenomics.00070.2017. - DOI - PubMed
    1. Pradère JP, Klein J, Grès S, Guigné C, Neau E, Valet P, Calise D, Chun J, Bascands JL, Saulnier-Blache JS, Schanstra JP. LPA1 receptor activation promotes renal interstitial fibrosis. J Am Soc Nephrol 18: 3110–3118, 2007. doi:10.1681/ASN.2007020196. - DOI - PubMed

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