scholarly journals Pharmacologically Inhibiting Glycogen Synthase Kinase-3β Ameliorates Renal Inflammation and Nephrotoxicity in an Animal Model of Cisplatin-Induced Acute Kidney Injury

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 887
Author(s):  
Chung-Hsi Hsing ◽  
Cheng-Chieh Tsai ◽  
Chia-Ling Chen ◽  
Yu-Hui Lin ◽  
Po-Chun Tseng ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Glycogen Synthase ◽  
Kidney Injury ◽  
Glycogen Synthase Kinase ◽  
Epithelial Cell Line ◽  
Chemokine Production ◽  
Renal Inflammation ◽  
Cisplatin Nephrotoxicity ◽  
Proximal Tubular ◽  
Gsk 3Β

The adverse effect of cisplatin administration causes acute kidney injury (AKI) following renal inflammation and nephrotoxicity, characterized by proximal tubular cell apoptosis and necrosis. Pro-apoptotic and pro-inflammatory roles of glycogen synthase kinase (GSK)-3β have been reported. This study investigated the therapeutic blockade of GSK-3β in cisplatin-induced AKI. A renal cisplatin nephrotoxicity model showed activation of GSK-3β in vivo, particularly in proximal tubular epithelial cells. Pharmacologically inhibiting GSK-3β abolished cisplatin nephrotoxicity, including proximal tubular injury, cell cytotoxicity, and biochemical dysfunction. Additionally, GSK-3β inhibitor treatment ameliorated renal inflammation by reducing immune cell infiltration, cell adhesion molecule expression, and pro-inflammatory cytokine/chemokine production. Cisplatin treatment caused GSK-3β activation in vitro in the human renal proximal tubular epithelial cell line HK-2, whereas either pharmacological administration of GSK-3β inhibitors or genetic transduction of GSK-3β short-hairpin RNA impeded cisplatin-induced cytotoxicity. These results indicate that cisplatin activates GSK-3β followed by GSK-3β-mediated renal inflammation and nephrotoxicity, contributing to AKI.

scholarly journals Inhibition of glycogen synthase kinase-3β prevents NSAID-induced acute kidney injury

2012 ◽  
Vol 81 (7) ◽  
pp. 662-673 ◽  
Author(s):  
Hao Bao ◽  
Yan Ge ◽  
Shougang Zhuang ◽  
Lance D. Dworkin ◽  
Zhihong Liu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Glycogen Synthase ◽  
Kidney Injury ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β

scholarly journals Glycogen Synthase Kinase-3 Signaling in Acute Kidney Injury

Nephron ◽  
2020 ◽  
Vol 144 (12) ◽  
pp. 609-612
Author(s):  
Abeda Jamadar ◽  
Reena Rao
Keyword(s):  
Acute Kidney Injury ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Clinical Syndrome ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Renal Tubular

Acute kidney injury (AKI) is a common clinical syndrome that involves renal tubular epithelial cell death and leads to acute decline in renal function. Improper tubular regeneration following AKI often leads to CKD. We discuss the role of a serine/threonine protein kinase called glycogen synthase kinase-3 (GSK3) in renal tubular injury and renal fibrosis. We also highlight the importance of GSK3 as a potential drug target in AKI patients and molecular mechanisms promoting tissue regeneration.

scholarly journals Glycogen synthase kinase‐3β inhibits tubular regeneration in acute kidney injury by a FoxM1‐dependent mechanism

2020 ◽  
Vol 34 (10) ◽  
pp. 13597-13608
Author(s):  
Sonali Sinha ◽  
Nidhi Dwivedi ◽  
James Woodgett ◽  
Shixin Tao ◽  
Christianna Howard ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Glycogen Synthase ◽  
Kidney Injury ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Dependent Mechanism

scholarly journals T95 nucleophosmin phosphorylation as a novel mediator and marker of regulated cell death in acute kidney injury

2020 ◽  
Vol 319 (3) ◽  
pp. F552-F561
Author(s):  
Zhiyong Wang ◽  
Mostafa Belghasem ◽  
Erdjan Salih ◽  
Joel Henderson ◽  
Chinaemere Igwebuike ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Mammalian Cells ◽  
Glycogen Synthase ◽  
Consensus Sequence ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Resting Cells ◽  
Free System ◽  
Gsk 3Β

The function of site-specific phosphorylation of nucleophosmin (NPM), an essential Bax chaperone, in stress-induced cell death is unknown. We hypothesized that NPM threonine 95 (T95) phosphorylation both signals and promotes cell death. In resting cells, NPM exclusively resides in the nucleus and T95 is nonphosphorylated. In contrast, phosphorylated T95 NPM (pNPM T95) accumulates in the cytosol after metabolic stress, in multiple human cancer cell lines following γ-radiation, and in postischemic human kidney tissue. Based on the T95 phosphorylation consensus sequence, we hypothesized that glycogen synthase kinase-3β (GSK-3β) regulates cytosolic NPM translocation by phosphorylating T95 NPM. In a cell-free system, GSK-3β phosphorylated a synthetic NPM peptide containing T95. In vitro, bidirectional manipulation of GSK-3β activity substantially altered T95 phosphorylation, cytosolic NPM translocation, and cell survival during stress, mechanistically linking these lethal events. Furthermore, GSK-3β inhibition in vivo decreased cytosolic pNPM T95 accumulation in kidney tissue after experimental ischemia. In patients with acute kidney injury, both cytosolic NPM accumulation in proximal tubule cells and NPM-rich intratubular casts were detected in frozen renal biopsy tissue. These observations show, for the first time, that GSK-3β promotes cell death partly by phosphorylating NPM at T95, to promote cytosolic NPM accumulation. T95 NPM is also a rational therapeutic target to ameliorate ischemic renal cell injury and may be a universal injury marker in mammalian cells.

scholarly journals Cisplatin nephrotoxicity is induced via poly(ADP-ribose) polymerase activation in adult zebrafish and mice

2020 ◽  
Vol 318 (5) ◽  
pp. R843-R854 ◽  
Author(s):  
Myoung-Jin Kim ◽  
Daeun Moon ◽  
Sumi Jung ◽  
Jehee Lee ◽  
Jinu Kim
Keyword(s):  
Acute Kidney Injury ◽  
Genetic Manipulation ◽  
Kidney Diseases ◽  
Parp Inhibitor ◽  
Periodic Acid ◽  
Kidney Injury ◽  
Adult Zebrafish ◽  
Cisplatin Nephrotoxicity ◽  
Alkaline Phosphatase Staining ◽  
Proximal Tubular

Cisplatin is a well-known chemotherapy medication used to treat numerous cancers. However, treatment with cisplatin in cancer therapy has major side effects, such as nephrotoxic acute kidney injury. Adult vertebrate kidneys are commonly used as models of cisplatin-induced nephrotoxic acute kidney injury. Embryonic zebrafish kidney is more simplified and is composed simply of two nephrons and thus is an excellent model for the investigation of cisplatin nephrotoxicity. Here, we developed a novel model to induce cisplatin nephrotoxicity in adult zebrafish and demonstrated that intraperitoneal injection of cisplatin caused a decline in kidney proximal tubular function based on fluorescein-labeled dextran uptake and alkaline phosphatase staining. We also showed that cisplatin induced histological injury of the kidney tubules, quantified by tubular injury scores on the periodic acid-Schiff-stained kidney sections. As shown in a mouse model of cisplatin-induced nephrotoxicity, the activation of poly(ADP-ribose) polymerase (PARP), an enzyme implicated in cisplatin-induced cell death, was markedly increased after cisplatin injection in adult zebrafish. Furthermore, pharmacological inhibition of PARP using a specific PARP inhibitor PJ 34 hydrochloride (PJ34) or 3-aminobenzamide ameliorated kidney proximal tubular functional and histological damages in cisplatin-injected adult zebrafish kidneys. Administration of a combination of PARP inhibitors PJ34 and 3-aminobenzamide additively protected renal function and histology in zebrafish and mouse models of cisplatin nephrotoxicity. In conclusion, these data suggest that adult zebrafish are not only suitable for drug screening and genetic manipulation but also useful as a simplified but powerful model to study the pathophysiology of cisplatin nephrotoxicity and establish new therapies for treating human kidney diseases.

scholarly journals Activation and involvement of p53 in cisplatin-induced nephrotoxicity

2007 ◽  
Vol 293 (4) ◽  
pp. F1282-F1291 ◽  
Author(s):  
Qingqing Wei ◽  
Guie Dong ◽  
Tianxin Yang ◽  
Judit Megyesi ◽  
Peter M. Price ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Gene Knockout ◽  
Kidney Injury ◽  
Protein Accumulation ◽  
Wild Type ◽  
Tubular Cells ◽  
Cisplatin Nephrotoxicity ◽  
Proximal Tubular ◽  
P53 Activation ◽  
Deficient Mice

Cisplatin, a widely used chemotherapy drug, induces acute kidney injury, which limits its use and efficacy in cancer treatment. However, the molecular mechanism of cisplatin-induced nephrotoxicity is currently unclear. Using pharmacological and gene knockout models, we now demonstrate a pathological role for p53 in cisplatin nephrotoxicity. In C57BL/6 mice, cisplatin treatment induced p53 phosphorylation and protein accumulation, which was accompanied by the development of acute kidney injury. p53 was induced in both proximal and distal tubular cells and partially colocalized with apoptosis. Pifithrin-α, a pharmacological inhibitor of p53, suppressed p53 activation and ameliorated kidney injury during cisplatin treatment. Moreover, cisplatin-induced nephrotoxicity was abrogated in p53-deficient mice. Compared with wild-type animals, p53-deficient mice showed a better renal function, less tissue damage, and fewer apoptotic cells. In addition, cisplatin induced less apoptosis in proximal tubular cells isolated from p53-deficient mice than the cells from wild-type animals. Together these results suggest the involvement of p53 in cisplatin-induced renal cell apoptosis and nephrotoxicity.

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