The protective role of tubular [beta]-catenin in acute kidney injury

Abstract

Acute kidney injury (AKI) is an abrupt decrease in kidney function due to septic and aseptic aetiologies. It is a common complication in hospitalized patients, especially critically ill patients, associated with high mortality and increased risk of developing chronic kidney disease. However, the pathophysiologic mechanisms of AKI are not well understood, and therapy remains reactive and non-specific. Thus, it is critical to decipher the molecular mechanisms driving the onset and propagation of AKI to find better treatment targets and improve clinical outcomes. Cell death and mitochondrial dysfunction play a decisional role in AKI. Apoptosis and necroptosis are two dominant cell death ways in AKI, which are highly regulated by AKT/p53 and RIP3/MLKL pathways. Mitochondria take part in a network of intracellular processes that regulate homeostasis. The kidney is the second most oxygen-demanding organ in the body, sensitive to blood oxygen depletion. Renal tubules are particularly vulnerable to cell death and mitochondrial dysfunction in AKI due to its high metabolic rate. β-catenin signalling is essential during kidney development in the embryonic stage, and in adulthood, Wnt/β-catenin signalling mediates mitochondrial dysfunction during chronic kidney fibrosis. However, little is known of the influence of β-catenin in AKI. Therefore, the scope of this work is to investigate: (i) the role of tubular β-catenin signalling in septic and aseptic AKI; and (ii) the associated modulating mechanism of tubular β-catenin signalling on mitochondrial dysfunction and cell death. I established an inducible mouse model of tubule-specific β-catenin overexpression (TubCat) and a model of tubule-specific β-catenin depletion (TubcatKO). These mouse strains were utilized to induce septic AKI by lipopolysaccharide (LPS) injection and aseptic AKI by bilateral ischemia-reperfusion. The rationale for this gain and loss of β-catenin function approach is to provide confirmatory data to delineate the specific role of this molecule in the kidney tubule. In both AKI models, tubular β-catenin stabilization in TubCat animals significantly reduced BUN/serum creatinine, acute tubular damage (NGAL-positive tubules), apoptosis (TUNEL-positive cells) and necroptosis (phosphorylation of MLKL and RIP3) through activating AKT phosphorylation and p53 suppression; enhanced mitochondrial biogenesis (increased PGC-1α and NRF1) and restored mitochondrial mass (increased TIM23) to re-establish mitochondrial homeostasis (increased fusion markers OPA1, MFN2, and decreased fission protein DRP1) through the FOXO3/PGC-1α signalling cascade. Conversely, kidney function loss and histological damage, tubular cell death, and mitochondrial dysfunction were all aggravated in TubCatKO mice. Mechanistically, β-catenin transfection maintained mitochondrial mass and activated PGC-1α via FOXO3 in LPS-exposed HK-2 cells. Specifically, co-immunoprecipitation identified a direct interaction between nuclear β-catenin and FOXO3 and ChIP assay showed that β-catenin enhanced the interaction between FOXO3 protein and the promoter region of PGC-1α genes in tubular cells. These findings provide evidence that tubular β-catenin mitigates cell death and restores mitochondrial homeostasis in AKI through activation of AKT/p53 signalling and the nuclear FOXO3/PGC-1α pathway. It is envisaged that these observations could pave the way for the development of future targets against Wnt/β-catenin signalling specifically in the kidney tubule to alleviate AKI.