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

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.

Direct Impairment of the Endothelial Function by Acute Indoxyl Sulfate through Declined Nitric Oxide and Not Endothelium-Derived Hyperpolarizing Factor or Vasodilator Prostaglandins in the Rat Superior Mesenteric Artery

“…To date, multiple studies have indicated that indoxyl sulfate recued endothelial nitric oxide synthase (eNOS)/NO signaling. [53][54][55][56][57] In addition, some studies have reported that indoxyl sulfate-induced alterations, including glial function 58) and mesangial cell proliferation, 59) are mediated by the COX-2-mediated mechanism. As NO and COX-derived prostanoids are also vasoactive and released by endothelium, we assessed the correlation among indoxyl sulfate, COX, and endotheliumdependent relaxation.…”

Indoxyl Sulfate Induces Renal Fibroblast Activation through a Targetable Heat Shock Protein 90-Dependent Pathway

“…Among a variety of uremic toxins, IS is of particular interest because its levels are markedly elevated in CKD [6] and it is hardly removed by conventional dialysis due to its protein-binding capacity [22]. Several studies have demonstrated that IS, at uremic concentration (100–500 μ M), exerts profibrotic and proinflammatory effects on mesangial [23] and tubular cells [24] and induces epithelial-to-mesenchymal transition in NRK-52E renal proximal tubular cells [25].…”

“…The IS proinflammatory effect was shown in several different cell types: endothelial cells [42], adipocytes [43], and glomerular [23] and renal tubular cells [29]; these studies recognized IS as an important mediator of cell dysfunction in promoting a persistent and systemic inflammatory state in CKD patients. In our experimental setting, we demonstrated that IS can stimulate MCP1 expression in renal fibroblasts and identified HSP90 as a possible shared pawn between IS-induced fibrosis and inflammation in renal fibroblasts.…”

Prostaglandins in the pathogenesis of kidney diseases

“…In obese db/db mice with type-2 diabetes, the level of mPGES-1 expression in glomeruli was remarkably higher, suggesting the potential contribution of mPGES-1 in glomerular diseases associated with type-2 diabetes [ 65 ]. In kidney cells, we also found that mPGES-1-derived PGE2 could activate Stat3 signaling to promote podocyte apoptosis [ 66 ], and the proliferation of mesangial cells triggered by uric acid and uremic toxin indoxyl sulfate was attenuated by silencing mPGES-1 [ 67 , 68 ]. However, in a UUO model, mPGES-1 was shown to exert a protective effect against renal fibrosis and inflammation [ 62 ].…”