Elsevier

Seminars in Nephrology

Volume 40, Issue 2, March 2020, Pages 126-137
Seminars in Nephrology

Wnt/β-Catenin in Acute Kidney Injury and Progression to Chronic Kidney Disease

https://doi.org/10.1016/j.semnephrol.2020.01.004Get rights and content

Summary: Acute kidney injury (AKI) portends a poor clinical prognosis and increases the risk for the development of chronic kidney disease (CKD). Currently, there are no therapies to treat AKI or prevent its progression to CKD. Wnt/β-catenin is a critical regulator of kidney development that is up-regulated after injury. Most of the literature support a beneficial role for Wnt/β-catenin in AKI, but suggest that this pathway promotes the progression of tubulointerstitial fibrosis, the hallmark of CKD progression. We review the role of Wnt/β-catenin in renal injury with a focus on its potential as a therapeutic target in AKI and in AKI to CKD transition.

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WNT/β-CATENIN SIGNALING

The protein β-catenin has dual functions, serving as both a structural protein and a transcription factor, and the specific role depends on its cellular location and the presence of Wnt ligands. Membrane-bound β-catenin plays a structural role as part of the adherens junction complex that, together with α-catenin and cadherins, mediate cell–cell interactions. In the uninjured kidney, cytosolic β-catenin usually is targeted for degradation by the destruction complex, consisting of axin,

WNT/β-CATENIN AND RENAL DEVELOPMENT

An extensive discussion of Wnt/β-catenin in renal development is beyond the scope of this article, and interested readers are directed to prior reviews.18,19 Wnt is one of many growth factors involved in development (eg, Notch, hedgehog) that subsequently become re-expressed after renal injury.20 An understanding of their biological actions in development may provide insights into their function in the injured kidney. The developing kidney requires finely controlled cellular communication

WNT/β-CATENIN AND KIDNEY INJURY

Wnt/β-catenin signaling is expressed at low levels in the uninjured adult kidney, primarily in the papilla, but this pathway is up-regulated in rodent models of acute and chronic renal injury.12,25,26 Wnt and β-catenin activity have been localized to the proximal tubule after the ischemia-reperfusion injury (IRI) model,12,27 a common rodent model of AKI involving temporary clamping of the renal pedicle. This signaling pathway also is present in the interstitium after IRI and unilateral ureteral

WNT/β-CATENIN AND AKI

AKI is a rapid decrease in renal function caused by many different injuries such as drugs, ischemia from cardiopulmonary bypass, sepsis, and toxins. The initial target of AKI is thought to be the renal tubules, particularly the proximal tubule and thick ascending limb, both of which are very metabolically active segments with reduced oxygen tensions.33 Injured tubular epithelial cells undergo cell death through a variety of processes (eg, apoptosis, necrosis, necroptosis), and even viable cells

MECHANISMS WHEREBY WNT/β-CATENIN IS PROTECTIVE IN AKI

There may be several mechanisms by which Wnt/β-catenin signaling protects renal tubules including modulation of apoptosis and survival pathways (Fig. 2). Mice containing a tubule-specific deletion of β-catenin sustained greater tubular apoptosis after IRI or folic acid administration.37 This increased apoptosis was associated with greater expression of Bcl-2–associated X protein (Bax), a pro-apoptotic protein in the Bcl-2 family that induces mitochondrial injury. In addition, the conditional

AKI TO CKD PROGRESSION AND WNT/β-CATENIN

Recent data suggest that there is a continuum between AKI and CKD. Although some patients have restoration of their serum creatinine after AKI, it is well recognized that patients with severe AKI are at increased risk for the development of CKD. In addition, patients with CKD resulting from diabetes, hypertension, or other insults are at increased risk for AKI. The mechanisms of AKI to CKD progression are not completely understood, but most of the attention has focused on persistent tubule

WNT/β-CATENIN SIGNALING IN CHRONIC KIDNEY INJURY

There are much more data on the role of Wnt/β-catenin signaling in AKI than in AKI to CKD transition. Because renal injury exists on a continuum between acute and chronic, an understanding of how this signaling pathway affects CKD has important treatment implications. Furthermore, growth factor pathways that are beneficial in AKI (eg, epidermal growth factor) may be deleterious in CKD.66,67 Many systemic inhibitors of Wnt/β-catenin ameliorate fibrosis in rodent models of CKD, implying that this

TUBULAR EPITHELIAL WNT/β-CATENIN SIGNALING AND CKD

Tubular epithelial β-catenin signaling is particularly important because of this cellular compartment's role in AKI to CKD progression. Several groups have generated transgenic mice in which the epithelial cells overexpress Wnt ligands. Overexpression of Wnt1 by proximal tubules was sufficient to cause tubulointerstitial fibrosis by paracrine signaling in fibroblasts/pericytes and without epithelial injury.72 Similarly, Wnt9a overexpression by hydrodynamic tail injection after IRI increased

WNT/β-CATENIN SIGNALING IN RENAL FIBROBLASTS/PERICYTES AND CKD

Tubulointerstitial fibrosis consists of extracellular matrix proteins such as collagen and fibronectin, and myofibroblasts are the main producers of extracellular matrix. Although there is some debate about the origin of myofibroblasts, most agree that resident fibroblasts and pericytes are stimulated by growth factors to transform into myofibroblasts. Wnt1 and Wnt4 both have been shown to promote myofibroblast transformation from fibroblast and pericyte precursors in vitro.28,72 As mentioned

WNT/β-CATENIN SIGNALING IN INFLAMMATORY CELLS AND CKD

Inflammatory cells are another important component and modulator of both AKI and CKD. Most of the attention has focused on macrophages, which are subtyped into many different subsets with different functions. Broadly speaking, they have been divided into the proinflammatory M1 (classically activated) and profibrotic M2 (alternatively activated).78 In AKI, the M1 macrophage phenotype initially predominates and clodronate depletion of macrophages at this stage is beneficial. By contrast, the M2

MODULATING WNT/β-CATENIN IN AKI: CHALLENGES AND OPPORTUNITIES

The preclinical data overwhelmingly suggest a strong protective role for Wnt/β-catenin signaling in AKI. Although one study did show a deleterious effect of β-catenin signaling in fibroblasts, this probably does not outweigh the beneficial effects in renal tubules in AKI based on the studies that used systemic inhibitors. Furthermore, there are data to suggest that augmenting Wnt/β-catenin signaling is beneficial when present both at the time of injury and when activated after the initial

MODULATING WNT/β-CATENIN IN AKI TO CKD PROGRESSION: CHALLENGES AND OPPORTUNITIES

Because most human AKI is difficult to prevent, treatment of severe AKI to prevent progression to CKD/ESRD is an attractive approach.85 Although AKI causes a huge burden acutely in terms of mortality and hospitalization duration, there is also a huge effect on health and health care costs once AKI progresses to CKD. The clear concern with augmenting Wnt/β-catenin in AKI to CKD progression is the detrimental effects of this pathway that have been shown in rodent CKD models. The general paradigm

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    Financial support: Supported by National Heart, Lung, Blood Institute grant 135790 (W.D.M.), VA merit grant 1I01BX003425-01A21 (L.S.G.), and National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK108968-01 (L.S.G.).

    Conflict of interest statement: Leslie S. Gewin is a consultant for Surrozen, which is interested in Wnt pathway activation to promote regeneration.

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