Tubular β-catenin alleviates mitochondrial dysfunction and cell death in acute kidney injury

Abstract

Mitochondria take part in a network of intracellular processes that regulate homeostasis. Defects in mitochondrial function are key pathophysiological changes during AKI. Although Wnt/β-catenin signaling mediates mitochondrial dysfunction in chronic kidney fibrosis, little is known of the influence of β-catenin on mitochondrial function in AKI. To decipher this interaction, we generated an inducible mouse model of tubule-specific β-catenin overexpression (TubCat), and a model of tubule-specific β-catenin depletion (TubcatKO), and induced septic AKI in these mice with lipopolysaccharide (LPS) and aseptic AKI with bilateral ischemia-reperfusion. In both AKI models, tubular β-catenin stabilization in TubCat animals significantly reduced BUN/serum creatinine, 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 signaling 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. Collectively, these findings provide evidence that tubular β-catenin mitigates cell death and restores mitochondrial homeostasis in AKI through the common mechanisms associated with activation of AKT/p53 and FOXO3/PGC-1α signaling pathways.

NAD Supplement Alleviates Intestinal Barrier Injury Induced by Ethanol Via Protecting Epithelial Mitochondrial Function

“…We found that short-term ethanol consumption can also damage intestinal mitochondria, and the mechanism may be related to the inhibition of intestinal mitochondrial biosynthesis. PGC-1α is generally regarded as the main regulator of mitochondrial biosynthesis [ 38 , 39 ]. Although PGC-1α has been reported in the literature to be abundantly expressed in IECs and to play an important role in protecting intestinal barrier function [ 40 ], the function of PGC-1α has not been reported in models of ethanol damage.…”

SKP alleviates the ferroptosis in diabetic kidney disease through suppression of HIF-1α/HO-1 pathway based on network pharmacology analysis and experimental validation.

“…ROS are small molecular substances mainly derived from the respiratory chain of the inner mitochondrial membrane (13). The ferroptosis process will produce a large amount of ROS, and renal tubules are one of the tissues with the highest content of mitochondria (14), which is more prone to oxidative stress and damage. Prior studies indicate that ferroptosis is the primary mode of death for renal tubular cells (15), exacerbating tubular injury and interstitial brosis in DKD(16).…”

SKP alleviates the ferroptosis in diabetic kidney disease through suppression of HIF-1α/HO-1 pathway based on network pharmacology analysis and experimental validation

“…ROS are small molecular substances mainly derived from the respiratory chain of the inner mitochondrial membrane [ 13 ]. The ferroptosis process will produce a large amount of ROS, and renal tubules are one of the tissues with the highest content of mitochondria [ 14 ], which is more prone to oxidative stress and damage. Prior studies indicate that ferroptosis is the primary mode of death for renal tubular cells [ 15 ], exacerbating tubular injury and interstitial fibrosis in DKD [ 16 ].…”