Background Acute kidney injury (AKI) is associated with a severe decline in kidney function caused by abnormalities within the podocytes' glomerular matrix. Recently, AKI has been linked to alterations in glycolysis and the activity of glycolytic enzymes, including pyruvate kinase M2 (PKM2). However, the contribution of this enzyme to AKI remains largely unexplored. Methods Cre-loxP technology was used to examine the effects of PKM2 specific deletion in podocytes on the activation status of key signaling pathways involved in the pathophysiology of AKI by lipopolysaccharides (LPS). In addition, we used lentiviral shRNA to generate murine podocytes deficient in PKM2 and investigated the molecular mechanisms mediating PKM2 actions in vitro. Results Specific PKM2 deletion in podocytes ameliorated LPS-induced protein excretion and alleviated LPS-induced alterations in blood urea nitrogen and serum albumin levels. In addition, PKM2 deletion in podocytes alleviated LPS-induced structural and morphological alterations to the tubules and to the brush borders. At the molecular level, PKM2 deficiency in podocytes suppressed LPS-induced inflammation and apoptosis. In vitro, PKM2 knockdown in murine podocytes diminished LPS-induced apoptosis. These effects were concomitant with a reduction in LPS-induced activation of β-catenin and the loss of Wilms’ Tumor 1 (WT1) and nephrin. Notably, the overexpression of a constitutively active mutant of β-catenin abolished the protective effect of PKM2 knockdown. Conversely, PKM2 knockdown cells reconstituted with the phosphotyrosine binding–deficient PKM2 mutant (K433E) recapitulated the effect of PKM2 depletion on LPS-induced apoptosis, β-catenin activation, and reduction in WT1 expression. Conclusions Taken together, our data demonstrates that PKM2 plays a key role in podocyte injury and suggests that targetting PKM2 in podocytes could serve as a promising therapeutic strategy for AKI. Trial registration Not applicable.
It is estimated that by 2050 nearly 2.5 billion people are projected to have some degree of hearing loss and at least 700 million will require hearing rehabilitation. Hearing loss can be classified into three groups: sensorineural, conductive, and mixed. Sensorineural hearing loss (SNHL) arises from the inability of the inner ear to convert fluid waves into neural electric signals because of injury to cochlear hair cells resulting in hair cell death. In addition, systemic chronic inflammation implicated in other pathologies may exacerbate cell death leading to SNHL. Phytochemicals have emerged as a possible solution because of the growing evidence of their anti-inflammatory, antioxidant, and anti-apoptotic properties. Ginseng and its bioactive molecules, ginsenosides, exhibit effects that suppress pro-inflammatory signaling, reactive oxygen species (ROS) generation, and protect against apoptosis. In the current study, we investigated the effects of ginsenoside Rc (G-Rc) on UB/OC-2 primary murine sensory hair cell survival and homeostasis in response to palmitate-induced injury. We demonstrated that at a human equivalent dose G-Rc promoted UB/OC-2 cell survival and cell cycle progression. Additionally, G-Rc enhanced the differentiation of UB/OC-2 cells into functional sensory hair cells. Importantly, G-Rc alleviated inflammation, oxidative stress, ER stress, and apoptosis induced by palmitate. The current study offers novel insights into the effects of G-Rc as a potential adjuvant for SNHL and warrants further studies elucidating the molecular mechanisms mediating the beneficial effects of G-Rc on cochlear hair cells.
By 2050, at least 700 million people will require hearing therapy while 2.5 billion are projected to suffer from hearing loss. Sensorineural hearing loss (SNHL) arises from the inability of the inner ear to convert fluid waves into neural electric signals because of injury to cochlear hair cells that has resulted in their death. In addition, systemic chronic inflammation implicated in other pathologies may exacerbate cell death leading to SNHL. Phytochemicals have emerged as a possible solution because of the growing evidence of their anti-inflammatory, antioxidant, and anti-apoptotic properties. Ginseng and its bioactive molecules, ginsenosides, exhibit effects that suppress pro-inflammatory signaling and protect against apoptosis. In the current study, we investigated the effects of ginsenoside Rc (G-Rc) on UB/OC-2 primary murine sensory hair cell survival in response to palmitate-induced injury. G-Rc promoted UB/OC-2 cell survival and cell cycle progression. Additionally, G-Rc enhanced the differentiation of UB/OC-2 cells into functional sensory hair cells and alleviated palmitate-induced inflammation, endoplasmic reticulum stress, and apoptosis. The current study offers novel insights into the effects of G-Rc as a potential adjuvant for SNHL and warrants further studies elucidating the molecular mechanisms.
In the last decade, development and regulation of brown adipose tissue (BAT) has gained traction due to its potential role in the protection against obesity and its associated disorders. Notably, BAT activity inversely correlates with overall adiposity. Brown fat‐like adipocytes, that express the brown adipocyte‐specific uncoupling protein 1, are interspersed in WAT of rodents and humans. These brown‐like adipocytes exhibit many of the morphological and biochemical characteristics of classical brown adipocytes. Remarkably, brown‐like transformation of WAT is associated with resistance to diet induced obesity in experimental mouse models. However, the mechanisms that regulate the browning of WAT remain incompletely understood. Recent studies have shown that inhibition of the glycolytic enzyme Pyruvate Kinase M2 (PKM2) promotes brown adipogenesis. Notably, PKM2 is an upstream regulator of the Wnt/β‐catenin. Although the molecular mechanisms are yet to be determined, recent studies have shown that the Wnt/β‐catenin regulates the differentiation of both, white and brown adipogenesis. Therefore, the main objective of the current study is to investigate the role of Wnt/β‐catenin in mediating PKM2’s function in in brown adipogenesis and function. We demonstrate that PKM2 deficiency and pharmacological inhibition enhances brown fat activity via modulation of the Wnt/β‐catenin signaling pathway. These findings identify PKM2 as a good target for therapeutic approaches aiming at overcoming the obesity epidemic and its comorbidities.
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