Lysophosphatidic Acid Promotes Epithelial–Mesenchymal Transition in Kidney Epithelial Cells via the LPAR1/MAPK-AKT/KLF5 Signaling Pathway in Diabetic Nephropathy

Abstract

The epithelial–mesenchymal transition (EMT) is a differentiation process associated with fibrogenesis in diabetic nephropathy (DN). Lysophosphatidic acid (LPA) is a small, naturally occurring glycerophospholipid implicated in the pathogenesis of DN. In this study, we investigated the role of LPA/LPAR1 signaling in the EMT of tubular cells as well as the underlying mechanisms. We observed a decrease in E-cadherin and an increase in vimentin expression levels in the kidney tubules of diabetic db/db mice, and treatment with ki16425 (LPAR1/3 inhibitor) inhibited the expression of these EMT markers. Ki16425 treatment also decreased the expression levels of the fibrotic factors fibronectin and alpha-smooth muscle actin (α-SMA) in db/db mice. Similarly, we found that LPA decreased E-cadherin expression and increased vimentin expression in HK-2 cells, which was reversed by treatment with ki16425 or AM095 (LPAR1 inhibitor). In addition, the expression levels of fibronectin and α-SMA were increased by LPA, and this effect was reversed by treatment with ki16425 and AM095 or by LPAR1 knockdown. Moreover, LPA induced the expression of the transcription factor, Krüppel-like factor 5 (KLF5), which was decreased by AM095 treatment or LPAR1 knockdown. The expression levels of EMT markers and fibrotic factors induced by LPA were decreased upon KLF5 knockdown in HK-2 cells. Inhibition of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and serine-threonine kinase (AKT) pathways decreased LPA-induced expression of KLF5 and EMT markers. In conclusion, these data suggest that LPA contributes to the pathogenesis of diabetic nephropathy by inducing EMT and renal tubular fibrosis via regulation of KLF5 through the LPAR1.

Cellular and Molecular Control of Lipid Metabolism in Idiopathic Pulmonary Fibrosis: Clinical Application of the Lysophosphatidic Acid Pathway

“…Of the LPA species, LPA (16:0) and LPA (18:0) increased soon (Day 1) after bleomycin treatment, followed 3 days later by an increase of LPA(18:1), LPA(18:2), and LPA(20:4) [144]. In kidney epithelial cells, stimulation of EMT (epithelial-mesenchymal transition) via the LPA1/MAPK-AKT/KLF5 signaling pathway has been reported, and a similar event may be occurring also in the lungs [145]. The LPA1/3 antagonist VPC12249 has been reported to have attenuated the pulmonary fibrosis in a mouse model of radiation lung fibrosis.…”

Downregulation of KLF5 by EBER1 via the ERK signaling pathway in EBV-positive nasopharyngeal carcinoma cells: implications for latent EBV infection

“…Our laboratory has previously demonstrated the inhibitory effect of EBV on the ERK signalling pathway in gastric cancer [37]. Additionally, published literature indicates that the ERK signalling pathway can induce KLF5 expression [38, 39, 49], with KLF5 acting as a downstream target of both ERK 1/2 and p38 MAPK pathways [40]. Based on this evidence, we hypothesized that EBER1, an EBV-encoded product, might contribute to KLF5 expression suppression by inhibiting the ERK signalling pathway.…”

Participation of Krüppel-like Factors in Atherogenesis

“…These pathways play an important role in cell proliferation, survival, and differentiation. Activation of these pathways leads to phosphorylation and activation of several transcription factors, including KLF5 [ 64 , 65 , 66 , 67 ]. Activation of the PI3K/Akt and MAPK pathways leads to increased KLF5 gene expression in VSMCs.…”