Abstract
Hyperuricemia is not only the main feature of gout but also a cause of gout-related organ injuries including glomerular hypertrophy and sclerosis. Uric acid (UA) has been proven to directly cause mesangial cell (MC) proliferation with elusive mechanisms. The present study was undertaken to examined the role of inflammatory cascade of COX-2/mPGES-1/PGE2 in UA-induced MC proliferation. In the dose- and time-dependent experiments, UA increased cell proliferation shown by the increased total cell number, DNA synthesis rate, and the number of cells in S and G2 phases in parallel with the upregulation of cyclin A2 and cyclin D1. Interestingly, UA-induced cell proliferation was accompanied with the upregulation of COX-2 and mPGES-1 at both mRNA and protein levels. Strikingly, inhibition of COX-2 via a specific COX-2 inhibitor NS-398 markedly blocked UA-induced MC proliferation. Meanwhile, UA-induced PGE2 production was almost entirely abolished. Furthermore, inhibiting mPGES-1 by a siRNA approach in MCs also ameliorated UA-induced MC proliferation in line with a significant blockade of PGE2 secretion. More importantly, in gout patients, we observed a significant elevation of urinary PGE2 excretion compared with healthy controls, indicating a translational potential of this study to the clinic. In conclusion, our findings indicated that COX-2/mPGES-1/PGE2 cascade activation mediated UA-induced MC proliferation. This study offered new insights into the understanding and the intervention of UA-related glomerular injury.
Highlights
Uric acid (UA) is an intermediary product of the purine degradation pathway in cells [1]
Hyperuricemia could contribute to the glomerular damage like glomerular hypertrophy [16], mesangial cell proliferation [9] and matrix deposition, glomerular sclerosis [17], and tubular interstitial injury [18]
Recent report indicated that UA has a direct role in promoting mesangial cell (MC) proliferation [9]
Summary
Uric acid (UA) is an intermediary product of the purine degradation pathway in cells [1]. Emerging evidence highly suggested that hyperuricemia was associated with the occurrence and progression of kidney injury in patients with gout [4, 5]. Patients with hyperuricemia often have glomerular hypertrophy and tubule interstitial injury independent of intrarenal crystal formation [6, 7]. UA was found to directly induce glomerular mesangial cell (MC) proliferation [9]. The UA-related mesangial cell proliferation might contribute www.impactjournals.com/oncotarget to the glomerular hypertrophy and sclerosis, which could result in the development and progression of renal injury. The detailed mechanism of UA-associated mesangial cell proliferation is still elusive, leading to the lack of effective targets in the prevention and treatment of hyperuricemia-related kidney disease
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