EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy

Abstract

Hyperuricemia is an independent risk factor for CKD and contributes to kidney fibrosis. In this study, we investigated the effect of EGF receptor (EGFR) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN induced by feeding a mixture of adenine and potassium oxonate, increased EGFR phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, accompanied by renal dysfunction and increased urine microalbumin excretion. Administration of gefitinib, a highly selective EGFR inhibitor, prevented renal dysfunction, reduced urine microalbumin, and inhibited activation of renal interstitial fibroblasts and expression of extracellular proteins. Gefitinib treatment also inhibited hyperuricemia-induced activation of the TGF-b1 and NF-kB signaling pathways and expression of multiple profibrogenic cytokines/chemokines in the kidney. Furthermore, gefitinib treatment suppressed xanthine oxidase activity, which mediates uric acid production, and preserved expression of organic anion transporters 1 and 3, which promotes uric acid excretion in the kidney of hyperuricemic rats. Thus, blocking EGFR can attenuate development of HN via suppression of TGF-b1 signaling and inflammation and promotion of the molecular processes that reduce uric acid accumulation in the body. Serum uric acid is enhanced in patients with CKD regardless of whether it is primary or secondary. Hyperuricemia-related diseases were historically viewed with limited interest. 1 However, increasing evidence has indicated that the increased level of uric acid is tightly associated with the development and progression of CKD as well as many other diseases, such as hypertension, cardiovascular diseases, and diabetes. [2][3][4][5][6][7] For example, a recent meta-analysis of a prospective cohort study showed a 12% rise in mortality for every 1-mg/dl rise in serum uric acid in persons with coronary heart disease. 8 Other pilot investigations indicate that lowering plasma uric acid concentrations slows and delays the development of CKD. [9][10][11][12][13][14][15] Thus, uric acid is likely an important mediator and risk marker in CKD.Uric acid is the final metabolic product of purine metabolism in humans and is excreted in urine. Serum uric acid levels are controlled by the balance of

The Epidermal Growth Factor Receptor: A Potential Therapeutic Target in Chronic Kidney Disease

“…Using this model, they demonstrated that blockage of EGFR by gefitinib, a drug that specially inhibits EGFR activation and is clinically used for treating various cancers, alleviated renal fibrosis and renal tubular injury and inhibited activation of renal interstitial fibroblast, a pathological process that initiates the development of renal fibrosis and promotes its progression. 4 Mechanistically, inhibition of EGFR abrogated the expression of TGF-β and phosphorylation of Smad3 (a downstream molecule of TGF-β), and blocked NF-kB pathway activation and macrophage infiltration in the kidney of hyperuricemic rat. 4 In addition, gfitinib treatment decreased release of various proinflammatory cytokines/chemokines including TGFα, interleukin 1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1) and RANTES.…”

“…4 Mechanistically, inhibition of EGFR abrogated the expression of TGF-β and phosphorylation of Smad3 (a downstream molecule of TGF-β), and blocked NF-kB pathway activation and macrophage infiltration in the kidney of hyperuricemic rat. 4 In addition, gfitinib treatment decreased release of various proinflammatory cytokines/chemokines including TGFα, interleukin 1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1) and RANTES. 4 Furthermore, blockage of EGFR reduced serum uric acid levels through inhibiting the activity of the enzyme xanthine oxidase, a key enzyme for the production of uric acid, as well as through preventing the downregulation of urate transporters, organic anion transporter 1 (OAT1) and OAT3.…”

“…8,9 Numerous studies have shown that EGFR activation contributes to chronic renal injury and glomerular sclerosis. 4,10 Intriguingly, a recent study by Liu et al 4 reported that EGFR activation was critically involved in uric acid-induced chronic renal injury in a rat model of hyperuricemic nephropathy. Using this model, they demonstrated that blockage of EGFR by gefitinib, a drug that specially inhibits EGFR activation and is clinically used for treating various cancers, alleviated renal fibrosis and renal tubular injury and inhibited activation of renal interstitial fibroblast, a pathological process that initiates the development of renal fibrosis and promotes its progression.…”

“…[1][2][3] Accumulating evidence has shown that hyperuricemia is tightly associated with the pathogenesis of CKD. [1][2][3][4] Hyperuricemic nephropathy is a condition characterized by glomerular hypertension, arteriolosclerosis, and tubule interstitial fibrosis. Prior studies demonstrate that decreasing uric acid levels delays the development of CKD and slows its progression and uric acid is an independent predictor of future development of CKD.…”

“…Prior studies demonstrate that decreasing uric acid levels delays the development of CKD and slows its progression and uric acid is an independent predictor of future development of CKD. [1][2][3][4] The mechanistic processes by which hyperuricemia induces chronic renal injury involve deposition of uric acid crystals in the collecting duct of the kidney, renal angiotension system activation, oxidative stress, tubular epithelial cell transition and inflammation.…”