IL‐1β functionally attenuates ABCG2 and PDZK1 expression in HK‐2 cells partially through NF‐ĸB activation

Abstract

Long‐standing untreated hyperuricemia could lead to gout. Several recent studies have demonstrated a significant decrease of serum urate during acute gout attack, which is an aseptic inflammation process focusing on IL‐1β. However, how IL‐1β, by itself, alters the expression and the functional activity of urate transporters in renal tubular epithelial cells is still unclear. Herein, we revealed that IL‐1β could attenuate the mRNA and protein levels of ABCG2, a major urate efflux pump, in HK‐2 cells by real‐time PCR and Western‐blot assays. Moreover, using an ABCG2 specific inhibitor and a new sensitive and specific detection system, it was found that IL‐1β also reduced the ABCG2 transporter activities. Incubation with specific inhibitors of the NF‐κB pathway partly dampened the inhibitory effect of IL‐1β on ABCG2, indicating that IL‐1β reduced the ABCG2 expression partially through the NF‐ĸB pathway. Furthermore, the decreased expression of PDZK1 induced by IL‐1β, which is dependent on the NF‐κB pathway, could account for the imbalance between the functions and expressions of ABCG2 on this status. These findings demonstrated a new role for IL‐1β, whereby it leads to the inhibition of ABCG2 in renal tubular epithelial cells; this new role probably does not encompass its involvement in the process of renal urate excretion mediated by inflammation. Therefore, other regulation mechanisms of urate reabsorption in renal tubular epithelial cells deserve to be examined in further studies.

Interleukin-37 contributes to the pathogenesis of gout by affecting PDZ domain-containing 1 protein through the nuclear factor-kappa B pathway

“…Prior work has highlighted the presence of increased levels of IL-1β, IL-6, IL-10, and TNF-α in synovial fluid samples from patients with GA. 6 Like IL-10 and TGF-β, IL-37 is an anti-inflammatory factor. 7 However, few studies have assessed how IL-37 is involved in the pathogenesis of gout.…”

“…It plays an important role in uric acid transport by changing the expression of PDZK1 through molecular signaling pathways such as the nuclear factor-jB (NF-jB) pathway. 6,7 Currently, the etiology of gout involves a variety of factors, including cytokines, susceptibility genes, and gene mutations 8,9 but its exact pathogenesis has not been elucidated. Its biochemical manifestations are disordered purine anabolism and reduced renal excretion of uric acid, resulting in elevated serum uric acid levels and deposition in some joints and tissues.…”

“… 4 Elevated levels of IL-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 have previously been identified in samples from patients with gouty arthritis (GA). 5 , 6 Recent studies have found that IL-37 has inhibitory effects on a variety of inflammatory factors, including toll-like receptor (TLR) ligands, IL-1β, TNF, and IL-12 in combination with IL-1β. It plays an important role in uric acid transport by changing the expression of PDZK1 through molecular signaling pathways such as the nuclear factor-κB (NF-κB) pathway.…”

“…It plays an important role in uric acid transport by changing the expression of PDZK1 through molecular signaling pathways such as the nuclear factor-κB (NF-κB) pathway. 6 , 7 …”

Research Advances in the Mechanisms of Hyperuricemia-Induced Renal Injury

“…GLUT9 acts as a transporter that reabsorbs both UA and glucose into tubular cells [ 26 ]. ABCG2, which was first found to be involved in the development of multidrug resistance in cancer cells, also takes part in the secretion of UA from proximal TECs through an ion pump [ 29 ]. Genetic defects or mutations in secretion-related transporters also contribute to hyperuricemia.…”