Lysophosphatidic Acid Is a Proinflammatory Stimulus of Renal Tubular Epithelial Cells

Abstract

Chronic kidney disease (CKD) refers to a spectrum of diseases defined by renal fibrosis, permanent alterations in kidney structure, and low glomerular-filtration rate. Prolonged epithelial-tubular damage involves a series of changes that eventually lead to CKD, highlighting the importance of tubular epithelial cells in this process. Lysophosphatidic acid (LPA) is a bioactive lipid that signals mainly through its six cognate LPA receptors and is implicated in several chronic inflammatory pathological conditions. In this report, we have stimulated human proximal tubular epithelial cells (HKC-8) with LPA and 175 other possibly pathological stimuli, and simultaneously detected the levels of 27 intracellular phosphoproteins and 32 extracellular secreted molecules with multiplex ELISA. This quantification revealed a large amount of information concerning the signaling and the physiology of HKC-8 cells that can be extrapolated to other proximal tubular epithelial cells. LPA responses clustered with pro-inflammatory stimuli such as TNF and IL-1, promoting the phosphorylation of important inflammatory signaling hubs, including CREB1, ERK1, JUN, IκΒα, and MEK1, as well as the secretion of inflammatory factors of clinical relevance, including CCL2, CCL3, CXCL10, ICAM1, IL-6, and IL-8, most of them shown for the first time in proximal tubular epithelial cells. The identified LPA-induced signal-transduction pathways, which were pharmacologically validated, and the secretion of the inflammatory factors offer novel insights into the possible role of LPA in CKD pathogenesis.

The Role of Autotaxin and LPA Signaling in Embryonic Development, Pathophysiology and Cancer

“…Moreover, LPA induced the phosphorylation of transcription factors JUN and CREB1 and signaling proteins IκBα and MEK1. Our results suggested that the JNK/c-JUN, MEK/ERK, NFκB, and CREB pathways are implicated in the production of some of the LPA-mediated secreted factors [24]. Furthermore, upon clustering of the 176 stimuli, LPA clustered with proinflammatory molecules such as IL-1α, IL-1β, IL-17α, TNFα and others, attributing to LPA a proinflammatory role.…”

“…These cells were exposed to LPA and 175 other inflammatory-immunological stimuli, and multiplex ELISA was performed. LPA was found to induce the secretion of CCL2, also known as monocyte chemoattractant protein 1 (MCP-1), CCL3, also known as macrophage inflammatory protein-1α (MIP-1α), IL-6, IL-8, CXCL10 and soluble ICAM1 [24]. Moreover, LPA induced the phosphorylation of transcription factors JUN and CREB1 and signaling proteins IκBα and MEK1.…”

Autotaxin and Lysophosphatidic Acid Signalling: the Pleiotropic Regulatory Network in Cancer

“…Examples of such transactivation are, for instance, LPAR-dependent G-protein activation of Src kinase, which then phosphorylates EGFR, or LPAR-based activation of the MAPK pathway, which in turn leads to production of heparinbinding EGF-like growth factor, which again activates EGFR, leading to activation of transcription factors, including those mentioned above (Umata et al, 2001;Shah et al, 2005;Liu et al, 2009a). The transcription factors then elicit expression of pro-inflammatory cytokines such as CCL2, CCL3, CXCL10, ICAM1, IL-6, and IL-8 by the target cells (Magkrioti et al, 2022).…”

Autotaxin as a novel biomarker of migraine

“…LPA exerts its function through speci c membrane receptors (LPARs), involved in several mechanisms, such as platelets aggregation, vascular tone control, in ammation, endothelial dysfunction, and neuropathic pain; among others [12][13][14]. As mentioned, the ATX-LPA axis has been described to modulate different processes that are involved in the development and evolution of migraines, such as vascular tone [15,16], in ammation [17,18], neuroin ammation [19], and neuronal excitation [20], and pain [21,22]. However, its implication in migraine has not been studied.…”