Wnt/β-catenin signaling in kidney injury and repair: a double-edged sword

Abstract

The Wnt/β-catenin signaling cascade is an evolutionarily conserved, highly complex pathway that is known to be involved in kidney injury and repair after a wide variety of insults. Although the kidney displays an impressive ability to repair and recover after injury, these repair mechanisms can be overwhelmed, leading to maladaptive responses and eventual development of chronic kidney disease (CKD). Emerging evidence demonstrates that Wnt/β-catenin signaling possesses dual roles in promoting repair/regeneration or facilitating progression to CKD after acute kidney injury (AKI), depending on the magnitude and duration of its activation. In this review, we summarize the expression, intracellular modification, and secretion of Wnt family proteins and their regulation in a variety of kidney diseases. We also explore our current understanding of the potential mechanisms by which transient Wnt/β-catenin activation positively regulates adaptive responses of the kidney after AKI, and discuss how sustained activation of this signaling triggers maladaptive responses and causes destructive outcomes. A better understanding of these mechanisms may offer important opportunities for designing targeted therapy to promote adaptive kidney repair/recovery and prevent progression to CKD in patients.

Figure 1. The principle of Wnt secretion and signaling. (A)

Wnt expression, modification and secretion. In Wnt producing cells, Wnt proteins are lipid modified in the lumen of endoplasmic reticulum (ER) by Porcupine and then transported to the Golgi, where they encounter Wntless (Wls). Supported by Wls, Wnt ligands are directly delivered to the plasma membrane through Trans-Golgi network (TGN). Wls is then taken up by the clathrin-mediated endocytosis and the retromer complex routes Wls back to the Golgi from the plasma membrane. (B) The principle of Wnt signaling. Once released from the producing cells, Wnt initiates signal by interacting with the Frizzled receptor and co-receptors LRP5/6 at the plasma membrane of target cells and activates Dsh. At Dsh level, Wnt signaling is branched into canonical and non-canonical pathways. Activation of the canonical Wnt signaling leads to β-catenin stabilization, accumulation and nuclear translocation, which enables β-catenin to influence the expression of downstream target genes. Non-canonical Wnt signaling invokes several β-catenin independent pathways via the activation of the Frizzled receptor. In Wnt/planar cell polarity (PCP) pathway, Dsh transfers signal to the small GTP-binding proteins Rho and Rac. In Wnt/Ca²⁺ pathway, the Frizzled receptor also interfaces with a trimeric G-protein and results in the release of calcium from ER. When concentration of calcium rises, protein kinase C (PKC) and calcineurin will be activated. Calcineurin induces the nuclear factor of activated T-cells (NFAT), which regulates cell fate and migration.

Figure 2. Wnt/β-catenin signaling facilitates adaptive repair after AKI

Following ischemic or toxic insults, kidneys possess an intrinsic ability to recover by undergoing adaptive repair and regeneration. (A) Injury phase. Shortly after AKI, tubular damage includes loss of brush border and apical-basal polarity, cell detachment, apoptosis and necrosis. Injury to capillary and infiltration of inflammatory cells are also evident. (B) Regeneration phase. Following the initial damage, peritubular fibroblasts are activated, and tubular cells undergo proliferation to repair and regeneration. (C) Recovery phase. Tubular cells re-differentiate, while interstitial fibroblasts and inflammatory cells are resolved and capillary integrity restored. Wnt/β-catenin signaling promotes adaptive repair after AKI by promoting tubular cells survival and mitigating damage in the injury phase, by stimulating tubular cell proliferation in the regeneration phase, and by facilitating the resolution of interstitial fibroblasts and restoring capillary integrity in the recovery phase.

Figure 3. Wnt/β-catenin signaling promotes maladaptive responses after chronic injury

Following chronic, repetitive or severe injury, kidneys endure maladaptive responses that lead to CKD after the initial attempts of repair have failed. Sustained, but not transient, activation of Wnt/β-catenin signaling is crucial in triggering such maladaptive responses and causing destructive outcomes. Sustained Wnt//b-catenin signaling causes uncontrolled fibroblast activation, renin-angiotensin system (RAS) activation, inflammation and excessive deposition of extracellular matrix (ECM). Hyperactive Wnt/β-catenin also induces Snial1, plasminogen activator inhibitor 1 (PAI-1), MMP-7, fibroblast-specific protein 1 (Fsp1) and multiple components of RAS, all of which are relevant to CKD progression.