Renalase Protects against Renal Fibrosis by Inhibiting the Activation of the ERK Signaling Pathways

Abstract

Renal interstitial fibrosis is a common pathway for the progression of chronic kidney disease (CKD) to end-stage renal disease. Renalase, acting as a signaling molecule, has been reported to have cardiovascular and renal protective effects. However, its role in renal fibrosis remains unknown. In this study, we evaluated the therapeutic efficacy of renalase in rats with complete unilateral ureteral obstruction (UUO) and examined the inhibitory effects of renalase on transforming growth factor-β1 (TGF-β1)-induced epithelial–mesenchymal transition (EMT) in human proximal renal tubular epithelial (HK-2) cells. We found that in the UUO model, the expression of renalase was markedly downregulated and adenoviral-mediated expression of renalase significantly attenuated renal interstitial fibrosis, as evidenced by the maintenance of E-cadherin expression and suppressed expression of α-smooth muscle actin (α-SMA), fibronectin and collagen-I. In vitro, renalase inhibited TGF-β1-mediated upregulation of α-SMA and downregulation of E-cadherin. Increased levels of Phospho-extracellular regulated protein kinases (p-ERK1/2) in TGF-β1-stimulated cells were reversed by renalase cotreatment. When ERK1 was overexpressed, the inhibition of TGF-β1-induced EMT and fibrosis mediated by renalase was attenuated. Our study provides the first evidence that renalase can ameliorate renal interstitial fibrosis by suppression of tubular EMT through inhibition of the ERK pathway. These results suggest that renalase has potential renoprotective effects in renal interstitial fibrosis and may be an effective agent for slowing CKD progression.

Blockade of enhancer of zeste homolog 2 alleviates renal injury associated with hyperuricemia

“…Inhibition of EZH2 abrogates activation of EGFR/ERK1/2 signaling in the kidney of hyperuricemic mice. Studies from our group and others have illustrated that activation of the EGFR/ERK1/2 signaling pathway is critically involved in the progression of renal interstitial fibrosis (64,72). Thus we ascertained whether EZH2 plays a role in the phosphorylation of EGFR and ERK1/2.…”

The Emerging Role of Innate Immunity in Chronic Kidney Diseases

“…The persistent activation of Wnt/β-catenin signaling promotes chronic kidney disease and renal fibrosis. In an experimental CKD model, Wnt1 induces the prorenin receptor in kidney tubular epithelial cells to amplify the Wnt/β-catenin mediated pro-fibrotic genes expression (TGF-β, fibronectin, collagen I, plasminogen activator inhibitor-1, matrix metalloproteinase 7) [72,73]. Furthermore, Wnt/β-catenin signaling plays a crucial role in podocyte dysfunction, proteinuria, and glomerulosclerosis, particularly in diabetic nephropathy and focal segmental glomerulosclerosis [74,75].…”

ROS-ERK Pathway as Dual Mediators of Cellular Injury and Autophagy-Associated Adaptive Response in Urinary Protein-Irritated Renal Tubular Epithelial Cells

“…As p62 is selectively incorporated into autophagosomes and is efficiently degraded by autophagy, the decreased expression of p62 indicates that autophagy degradation is not affected by ERK pathway. Meanwhile, the accumulation of LC3-II suggests autophagy is activated [ 14 ]. However, the increased dose of LC3-II was reverted and p62 returned to normal levels under stimulation of U0126, which inhibited ERK pathway effectively.…”

“…However, the role of ERK pathway in renal injury is still controversial until now. The ERK pathway has proved to be a pathogenic factor in various disease models, such as cystic kidney diseases [ 11 ], kidney stones [ 12 ], and unilateral ureter obstruction kidneys [ 13 , 14 ]. More directly, Reich et al indicated that the ERK pathway mediates the albumin-induced toxicity of TECs [ 15 ].…”