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

Donghee Kim,Yoon Sin Oh,Hee-Sook Jun,Hui Ying Li,Jong Han Lee

doi:10.1038/s12276-019-0217-3

Abstract

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.

Highlights

Diabetic nephropathy (DN) is a well-known microvascular complication in patients with diabetes and a common cause of end-stage renal disease worldwide, contributing to the overall morbidity and mortality of patients with diabetes[1,2].Glomerular mesangial cells, one of the major types of resident renal cells, are involved in the processes of DN
Lysophosphatidic acid (LPA) induces mesangial cell proliferation SV40 MES13 cells were treated with different doses (0.1, 1, or 10 μM) of LPA, and the viability was measured using
Because LPA is expressed at high levels in the glomeruli of diabetic mice[12], we examined the proliferation of cells in the kidney cortex of wild-type and diabetic db/db mice

Summary

Introduction

Glomerular mesangial cells, one of the major types of resident renal cells, are involved in the processes of DN. Mesangial cell proliferation is stimulated in the early stage. Kim et al Experimental & Molecular Medicine (2019) 51:18 as proliferation, survival, and migration, via G proteincoupled receptors (GPCRs; LPA receptors 1–6)[7]. LPA induces the proliferation of different types of cells[8,9,10,11]. LPA induces fibrosis in SV40 MES13 cells, and the inhibition of LPA receptor 1 (LPAR1) signaling ameliorates DN in diabetic db/db mice[14]. These findings suggest the involvement of LPA in the hyperproliferation of renal cells. We sought to determine the underlying mechanisms to obtain a better understanding of the pathophysiology of the initial stage of DN using an animal model of type 2 diabetes and an in vitro model

Methods

Results

Conclusion