Pharmacologic Targeting of BET Proteins Attenuates Hyperuricemic Nephropathy in Rats

Abstract

Hyperuricemia is an independent risk factor for renal damage and promotes the progression of chronic kidney disease. In this study, we investigated the effect of I-BET151, a small-molecule inhibitor targeting the bromodomain and extraterminal (BET) proteins, on the development of hyperuricemic nephropathy (HN), and the mechanisms involved. Expression levels of bromodomain-containing protein 2 and 4, but not 3 were increased in the kidney of rats with HN; administration of I-BET151 effectively prevented renal dysfunction, decreased urine microalbumin, and attenuated renal fibrosis as indicated by reduced activation of renal interstitial fibroblasts and expression of fibronectin and collagen I in HN rats. Mechanistic studies show that I-BET151 treatment inhibited transition of renal epithelial cells to a mesenchymal cell type as evidenced by preservation of E-cadherin and reduction of vimentin expression. This was coincident with reduced expression of TGF-β1 and dephosphorylation of Smad3 and ERK1/2. I-BET151 was also effective in inhibiting phosphorylation of NF-κB, expression of multiple cytokines and chemokines, and infiltration of macrophages to the injured kidney. Although there were increased serum levels of uric acid and xanthine oxidase, an enzyme that catalyzes production of uric acid, and decreased expression of renal organic anion transporter 1 and 3 that promote urate excretion in the model of HN, and reduced expression levels of urine uric acid, I-BET151 treatment did not affect these responses. Collectively, our results indicate that I-BET151 alleviates HN by inhibiting epithelial to mesenchymal transition and inflammation in association with blockade of TGF-β, ERK1/2 and NF-κB signaling.

Histone Acetylation and Modifiers in Renal Fibrosis

“…Moreover, I-BET151 was effective in inhibiting the activation of transcription factors and growth factor receptors, such as c-Myc, P53, EGFR, and PDGFR, and reduced cell cycle arrested at G2/M phase ( Xiong et al, 2016 ). Recently, we further examined the effect of I-BET151 on the development of hyperuricemic nephropathy (HN) in a rat model and found that expression of Brd2 and Brd4, but not that of Brd3 was elevated in the injured kidney ( Xiong et al, 2021 ). Treatment with I-BET151 significantly prevented renal dysfunction, decreased urine microalbumin, and attenuated renal fibrosis.…”

“…Treatment with I-BET151 significantly prevented renal dysfunction, decreased urine microalbumin, and attenuated renal fibrosis. Furthermore, I-BET151 reduced expression of TGF-β1, inhibited dephosphorylation of Smad3 and ERK1/2 and NF-kB, and suppressed inflammatory response in the kidney ( Xiong et al, 2021 ). Although we detected an increase in serum levels of uric acid and xanthine oxidase, an enzyme that catalyzes production of uric acid, and a decrease in the expression of renal organic anion transporter 1 and 3, which promote urate excretion in the model of HN, I-BET151 treatment did not affect these responses ( Xiong et al, 2021 ).…”

“…Furthermore, I-BET151 reduced expression of TGF-β1, inhibited dephosphorylation of Smad3 and ERK1/2 and NF-kB, and suppressed inflammatory response in the kidney ( Xiong et al, 2021 ). Although we detected an increase in serum levels of uric acid and xanthine oxidase, an enzyme that catalyzes production of uric acid, and a decrease in the expression of renal organic anion transporter 1 and 3, which promote urate excretion in the model of HN, I-BET151 treatment did not affect these responses ( Xiong et al, 2021 ). These data suggest that Brd proteins may be involved in the mechanism leading to renal inflammation and fibrosis, but not associated with alteration of serum uric acid levels.…”

Astragaloside IV improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiota

“…Hyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia ( Dalbeth et al, 2021 ; Xiong et al, 2021 ). Excessive urinary acid deposition in the kidneys traditionally induces hyperuricemic nephropathy ( Johnson et al, 2018 ).…”

The Rho kinase signaling pathway participates in tubular mitochondrial oxidative injury and apoptosis in uric acid nephropathy

“…Various studies have shown that the development and progression of HN can occur through multiple mechanisms that are independent of acid crystal formation, such as promoting autophagy and NLRP3-mediated inflammation, 9 , 10 inhibiting transforming growth factor (TGF)-β, extracellular signal-regulated kinase 1/2 (ERK1/2), and nuclear factor (NF)-κB signaling pathways. 11 Hyperuricemia can cause oxidative stress that induces the overproduction of mitochondrial reactive oxygen species (ROS) in renal tubular epithelial cells, which play an important role in the pathogenesis of HN tubulointerstitial fibrosis. 12 Oxidative stress that is generated by monosodium urate (MSU) crystals promotes renal cell apoptosis, which is induced through the mitochondrial caspase-dependent apoptosis pathway.…”