Cell density-dependent expression of EDG family receptors and mesangial cell proliferation: role in lysophosphatidic acid-mediated cell growth

Xing, Yiding; Ganji, Shobha H.; Noh, Jung Won; Kamanna, Vaijinath S.

doi:10.1152/ajprenal.00342.2003

Cited by 13 publications

(4 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, additional studies on the hyperproliferative factors and the molecular mechanisms involved are needed to develop the most efficient and effective treatment strategy for DN. According to several studies 9,10,28 , including the present study, LPA exerts a pro-proliferative effect on renal mesangial cells. Moreover, in our previous study, the kidney cortex of diabetic mice showed proliferative activity with high levels of LPA 12 .…”

Section: Discussionsupporting

confidence: 62%

Lysophosphatidic acid increases mesangial cell proliferation in models of diabetic nephropathy via Rac1/MAPK/KLF5 signaling

Kim

Lee

et al. 2019

Exp Mol Med

View full text Add to dashboard Cite

Mesangial cell proliferation has been identified as a major factor contributing to glomerulosclerosis, which is a typical symptom of diabetic nephropathy (DN). Lysophosphatidic acid (LPA) levels are increased in the glomerulus of the kidney in diabetic mice. LPA is a critical regulator that induces mesangial cell proliferation; however, its effect and molecular mechanisms remain unknown. The proportion of α-SMA+/PCNA+ cells was increased in the kidney cortex of db/db mice compared with control mice. Treatment with LPA concomitantly increased the proliferation of mouse mesangial cells (SV40 MES13) and the expression of cyclin D1 and CDK4. On the other hand, the expression of p27Kip1 was decreased. The expression of Krüppel-like factor 5 (KLF5) was upregulated in the kidney cortex of db/db mice and LPA-treated SV40 MES13 cells. RNAi-mediated silencing of KLF5 reversed these effects and inhibited the proliferation of LPA-treated cells. Mitogen-activated protein kinases (MAPKs) were activated, and the expression of early growth response 1 (Egr1) was subsequently increased in LPA-treated SV40 MES13 cells and the kidney cortex of db/db mice. Moreover, LPA significantly increased the activity of the Ras-related C3 botulinum toxin substrate (Rac1) GTPase in SV40 MES13 cells, and the dominant-negative form of Rac1 partially inhibited the phosphorylation of p38 and upregulation of Egr1 and KLF5 induced by LPA. LPA-induced hyperproliferation was attenuated by the inhibition of Rac1 activity. Based on these results, the Rac1/MAPK/KLF5 signaling pathway was one of the mechanisms by which LPA induced mesangial cell proliferation in DN models.

show abstract

Section: Discussionsupporting

confidence: 62%

Lysophosphatidic acid increases mesangial cell proliferation in models of diabetic nephropathy via Rac1/MAPK/KLF5 signaling

Kim

Lee

et al. 2019

Exp Mol Med

View full text Add to dashboard Cite

show abstract

“…Six G protein-coupled receptors specific for LPA are distributed widely in animal tissues and organs (Ishii et al, 2009;Noguchi et al, 2009). In the kidney, LPA 1 , LPA 2 , LPA 3 and LPA 4 have been characterized, and their physiological and pathophysiological roles were postulated in the excretion of wastes (Xing et al, 2004;Pradère et al, 2008). In fact, LPA stimulated the proliferation and contraction of rat glomerular mesangial cells through activation of an LPA receptor (Inoue et al, 1995a,b).…”

Section: Introductionmentioning

confidence: 99%

Presence of bioactive lysophosphatidic acid in renal effluent of rats with unilateral ureteral obstruction

et al. 2011

View full text Add to dashboard Cite

“…The pathological features of the glomeruli during the progression of DN include mesangial expansion, thickening of the basement membrane, loss of podocytes, and glomerulosclerosis [ 3 , 33 ]. Several studies, including our previous report, have demonstrated that LPA induces the hyperproliferation of mesangial cells [ 7 , 34 – 36 ], and that the pharmacological blockade of LPA/LPAR signaling inhibits renal fibrosis and improves DN in diabetic mice [ 10 , 11 , 37 ]. Consistent with these reports, it has been demonstrated that the levels of LPA are significantly increased in the glomeruli of diabetic mice [ 38 , 39 ] and high-fat diet-induced obese mice [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ChREBP ubiquitination via the ROS/Akt-dependent downregulation of Smurf2 contributes to lysophosphatidic acid-induced fibrosis in renal mesangial cells

Lee

2022

J Biomed Sci

View full text Add to dashboard Cite

Background Mesangial cell fibrosis, a typical symptom of diabetic nephropathy (DN), is a major contributor to glomerulosclerosis. We previously reported that the pharmacological blockade of lysophosphatidic acid (LPA) signaling improves DN. Although LPA signaling is implicated in diabetic renal fibrosis, the underlying molecular mechanisms remain unclear. Here, the role of carbohydrate-responsive element-binding protein (ChREBP) in LPA-induced renal fibrosis and the underlying mechanisms were investigated. Methods Eight-week-old wild-type and db/db mice were intraperitoneally injected with the vehicle or an LPAR1/3 antagonist, ki16425 (10 mg/kg), for 8 weeks on a daily basis, following which the mice were sacrificed and renal protein expression was analyzed. SV40 MES13 cells were treated with LPA in the presence or absence of ki16425, and the expression of ChREBP and fibrotic factors, including fibronectin, TGF-β, and IL-1β, was examined. The role of ChREBP in the LPA-induced fibrotic response was investigated by ChREBP overexpression or knockdown. The involvement of Smad ubiquitination regulatory factor-2 (Smurf2), an E3 ligase, in LPA-induced expression of ChREBP and fibrotic factors was investigated by Smurf2 overexpression or knockdown. To identify signaling molecules regulating Smurf2 expression by LPA, pharmacological inhibitors such as A6370 (Akt1/2 kinase inhibitor) and Ly 294002 (PI3K inhibitor) were used. Results The renal expression of ChREBP increased in diabetic db/db mice, and was reduced following treatment with the ki16425. Treatment with LPA induced the expression of ChREBP and fibrotic factors, including fibronectin, TGF-β, and IL-1β, in SV40 MES13 cells, which were positively correlated. The LPA-induced expression of fibrotic factors increased or decreased following ChREBP overexpression and knockdown, respectively. The production of reactive oxygen species (ROS) mediated the LPA-induced expression of ChREBP and fibrotic factors, and LPA decreased Smurf2 expression via Traf4-mediated ubiquitination. The LPA-induced expression of ubiquitinated-ChREBP increased or decreased following Smurf2 overexpression and knockdown, respectively. Additionally, Smurf2 knockdown significantly increased the expression of ChREBP and fibrotic factors. The pharmacological inhibition of Akt signaling suppressed the LPA-induced alterations in the expression of ChREBP and Smurf2. Conclusion Collectively, the results demonstrated that the ROS/Akt-dependent downregulation of Smurf2 and the subsequent increase in ChREBP expression might be one of the mechanisms by which LPA induces mesangial cell fibrosis in DN.

show abstract

Cell density-dependent expression of EDG family receptors and mesangial cell proliferation: role in lysophosphatidic acid-mediated cell growth

Cited by 13 publications

References 47 publications

Lysophosphatidic acid increases mesangial cell proliferation in models of diabetic nephropathy via Rac1/MAPK/KLF5 signaling

Lysophosphatidic acid increases mesangial cell proliferation in models of diabetic nephropathy via Rac1/MAPK/KLF5 signaling

Presence of bioactive lysophosphatidic acid in renal effluent of rats with unilateral ureteral obstruction

Inhibition of ChREBP ubiquitination via the ROS/Akt-dependent downregulation of Smurf2 contributes to lysophosphatidic acid-induced fibrosis in renal mesangial cells

Contact Info

Product

Resources

About