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.

Targeted treatment of rat AKI induced by rhabdomyolysis using BMSC derived magnetic exosomes and its mechanism

“…In addition, the WNT/b-catenin pathway is briey activated aer AKI and has been identied as a protective response that minimizes cell damage by promoting renal tubular repair and regeneration. 63 The WNT/b-catenin pathway is reactivated aer renal injury, participating in the occurrence and development of renal brosis 64,65 and playing a key role in promoting kidney repair and regeneration. 66 For example, WNT agonists improve kidney regeneration and function, while reducing inammation and oxidative stress in the kidneys aer I/R.…”

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 fibrosis in DKD [ 16 ].…”