Wnt/β-catenin links oxidative stress to podocyte injury and proteinuria

Abstract

Podocyte injury is the major cause of proteinuria in primary glomerular diseases. Oxidative stress has long been thought to play a role in triggering podocyte damage; however, the underlying mechanism remains poorly understood. Here we show that the Wnt/b-catenin pathway is involved in mediating oxidative stress-induced podocyte dysfunction. Advanced oxidation protein products, a marker and trigger of oxidative stress, were increased in the serum of patients with chronic kidney disease and correlated with impaired glomerular filtration, proteinuria, and circulating level of Wnt1. Both serum from patients with chronic kidney disease and exogenous advanced oxidation protein products induced Wnt1 and Wnt7a expression, activated b-catenin, and reduced expression of podocyte-specific markers in vitro and in vivo. Blockade of Wnt signaling by Klotho or knockdown of b-catenin by shRNA in podocytes abolished b-catenin activation and the upregulation of fibronectin, desmin, matrix metalloproteinase-9, and Snail1 triggered by advanced oxidation protein products. Furthermore, conditional knockout mice with podocyte-specific ablation of b-catenin were protected against podocyte injury and albuminuria after treatment with advanced oxidation protein products. The action of Wnt/b-catenin was dependent on the receptor of advanced glycation end products (RAGE)mediated NADPH oxidase induction, reactive oxygen species generation, and nuclear factor-kB activation. These studies uncover a novel mechanistic linkage of oxidative stress, Wnt/b-catenin activation, and podocyte dysfunction.

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

“…β‐catenin is the downstream effector of Wnt signalling in tubular cell senescence, podocyte dedifferentiation and fibroblast activation . Although β‐catenin expression is silent in normal adult kidneys, it is reactivated at an early stage and keeps activation in the progression of CKD .…”

“…Protein expression levels were analysed by Western blot analysis as described previously . The primary antibodies used were as follows: anti‐SDF‐1α (ab25117; Abcam), anti‐fibronectin (F3648; Sigma‐Aldrich), anti‐α‐SMA (ab5694; Abcam), anti‐collagen I (ab34710; Abcam), anti‐vimentin (SAB1305447, Sigma‐Aldrich), anti‐CXCR4 (BA0747‐2; Boster), anti‐p‐GSK3β (ser 9) (5558; Cell Signaling Technology), anti‐β‐catenin (610 154; BD Transduction Laboratories), anti‐PAI‐1 (AF3828; R&D Systems), anti‐snail1 (ab180714; Abcam), anti‐MMP‐7 (104 658; GTX), anti‐E‐cadherin (3195; Cell Signaling Technology), anti‐active β‐catenin (19807s; Cell Signaling Technology), anti‐Kim1 (BA3537; Boster, Wuhan, China), anti‐α‐tubulin (RM2007, Ray Antibody Biotech, Beijing, China) and p‐STAT antibody sampler kit (9914; Cell Signaling Technology), p‐JAK family antibody sampler kit (97 999; Cell Signaling Technology), STAT antibody sampler kit (9939; Cell Signaling Technology) and anti‐GAPDH (RM2000, Ray Antibody Biotech, Beijing, China).…”

“…Upon the binding of Wnt ligands to the receptors frizzled (Fzd) and lipoprotein receptor–related protein (LRP) 5/6, GSK3β activity is repressed, and then, β‐catenin would be released and activated to trigger cell injury and renal fibrosis. Although β‐catenin could be up‐regulated in multiple cells such as podocytes, interstitial fibroblasts, endothelial cells and inflammatory cells, it is predominantly localized in renal tubular cells in injured kidneys . These observations suggest the potential relationship between CXCR4 and β‐catenin in renal tubular cell injury and fibrosis.…”

“…Different from its silent expression in normal adult's kidneys, Wnt/β‐catenin signalling is dramatically up‐regulated in CKD‐affected kidneys. The activation of Wnt/β‐catenin signalling is highly associated with oxidative stress, inflammation and cellular senescence . Upon the binding of Wnt ligands to the receptors frizzled (Fzd) and lipoprotein receptor–related protein (LRP) 5/6, GSK3β activity is repressed, and then, β‐catenin would be released and activated to trigger cell injury and renal fibrosis.…”

Sonic hedgehog connects podocyte injury to mesangial activation and glomerulosclerosis

“…To identify the upstream signal responsible for Shh induction in podocytes, we examined the potential role of Wnt ligands using cultured podocytes in vitro, because earlier studies showed that this signal cascade is activated in podocytes after injury (22,23). As shown in Figure 1, D and E, multiple Wnt ligands, either alone or in combination, induced Shh expression in cultured mouse podocytes.…”