Uric Acid Induces Renal Inflammation via Activating Tubular NF-κB Signaling Pathway

Abstract

Inflammation is a pathologic feature of hyperuricemia in clinical settings. However, the underlying mechanism remains unknown. Here, infiltration of T cells and macrophages were significantly increased in hyperuricemia mice kidneys. This infiltration of inflammatory cells was accompanied by an up-regulation of TNF-α, MCP-1 and RANTES expression. Further, infiltration was largely located in tubular interstitial spaces, suggesting a role for tubular cells in hyperuricemia-induced inflammation. In cultured tubular epithelial cells (NRK-52E), uric acid, probably transported via urate transporter, induced TNF-α, MCP-1 and RANTES mRNA as well as RANTES protein expression. Culture media of NRK-52E cells incubated with uric acid showed a chemo-attractive ability to recruit macrophage. Moreover uric acid activated NF-κB signaling. The uric acid-induced up-regulation of RANTES was blocked by SN 50, a specific NF-κB inhibitor. Activation of NF-κB signaling was also observed in tubule of hyperuricemia mice. These results suggest that uric acid induces renal inflammation via activation of NF-κB signaling.

Use of urinary metabolomics to evaluate the effect of hyperuricemia on the kidney

“…Hyperuricemia plays a significant role in renal injury; however, the detailed mechanisms remain unclear. Uric acid induces chemokines such as MCP-1 in the kidney and cyclooxygenase 2 in blood vessels (Kang et al, 2002;Zhou et al, 2012). Recently, uric acid was found to induce renal inflammation via NF-κB signaling (Suganuma et al, 2002).…”

Hyperuricemia and chronic kidney disease: an enigma yet to be solved

“…[46][47][48] UA crystals adhere to the surface of renal epithelial cells and may induce an acute local inflammatory response. 49 Interestingly, UA induces phenotypic transition of renal tubular cells suggesting a novel potential mechanism of CKD. 50 Apart from the increased risk of developing kidney stones, such effects seem to contribute to a decrease in GFR aggravated by the presence of hypertension.…”

Independent associations of urine neutrophil gelatinase–associated lipocalin and serum uric acid with interstitial fibrosis and tubular atrophy in primary glomerulonephritis

“…In experimental animals, hyperuricemia could induce endothelial dysfunction and vascular smooth muscle proliferation leading to secondary tubulointerstitial injury through reductions in GFR and ischemia. 4,10 Recent studies have also suggested that UA may act directly on renal tubules by stimulating cytokines production 26 and epithelial-to-mesenchymal transition, 13 which are key events in renal fibrosis. A primary role of UA on the renal tubules is further supported by the observation that phenotypic transition of the renal tubules in hyperuricemia occurred before the development of GFR reduction and that significant tubulointerstitial fibrosis could be ameliorated by lowering UA.…”