Indoxyl Sulfate Induces Mesangial Cell Proliferation via the Induction of COX-2.

Shuzhen Li,Aihua Zhang,Wei Gong,Jing Yu,Yue Zhang,Songming Huang,Harr-Keshauve Mungun,Weiwei Xia,Zhanjun Jia,Sijie Cheng,Zhenzhen Sun

doi:10.1155/2016/5802973

Shuzhen Li, Aihua Zhang + Show 9 more

Open Access

https://doi.org/10.1155/2016/5802973

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Abstract

Indoxyl sulfate (IS) is one of important uremic toxins and is markedly accumulated in the circulation of end stage renal disease (ESRD) patients, which might contribute to the damage of residual nephrons and progressive loss of residual renal function (RRF). Thus this study was undertaken to investigate the role of IS in modulating mesangial cell (MC) proliferation and the underlying mechanism. The proliferation of MCs induced by IS was determined by cell number counting, DNA synthase rate, and cell cycle phase analysis. COX-2 expression was examined by Western blotting and qRT-PCR, and a specific COX-2 inhibitor NS398 was applied to define its role in IS-induced MC proliferation. Following IS treatment, MCs exhibited increased total cell number, DNA synthesis rate, and number of cells in S and G2 phases paralleled with the upregulation of cyclin A2 and cyclin D1. Next, we found an inducible inflammation-related enzyme COX-2 was remarkably enhanced by IS, and the inhibition of COX-2 by NS398 significantly blocked IS-induced MC proliferation in line with a blockade of PGE2 production. These findings indicated that IS could induce MC proliferation via a COX-2-mediated mechanism, providing new insights into the understanding and therapies of progressive loss of RRF in ESRD.

Highlights

Preservation of residual renal function (RRF) is important for predialysis end stage renal disease (ESRD) patients and for the patients undergoing the dialysis
RRF in dialysis patients is pretty helpful in small-solute clearance, fluid balance, phosphorus control, and removal of middle-molecular uremic toxins, especially for the toxins relying on renal metabolism or tubular secretion, such as indoxyl sulfate (IS) [2, 4]
To investigate whether IS could induce mesangial cell (MC) proliferation, we treated the MCs with IS at the doses of 250 μM and 500 μM, respectively

Summary

Introduction

Preservation of residual renal function (RRF) is important for predialysis ESRD patients and for the patients undergoing the dialysis. RRF is a well-established predictor of the outcome and survival rate in dialysis patients [1]. RRF in dialysis patients is pretty helpful in small-solute clearance, fluid balance, phosphorus control, and removal of middle-molecular uremic toxins, especially for the toxins relying on renal metabolism or tubular secretion, such as indoxyl sulfate (IS) [2, 4]. IS has been shown to have many pathological roles in uremia-related organ injuries. It can increase the production of reactive oxygen species (ROS) and cause vascular wall remodeling and extracellular matrix deposition [13]. The MC proliferation and subsequent matrix synthesis could result in the glomerular impairment and RRF loss. Mediators of Inflammation the role of IS in mediating MC proliferation still needs evidence

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