Title: Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth
Authors: Thilakasiri, P
Huynh, J
Poh, AR
Tan, CW
Nero, TL
Tran, K
Parslow, AC
Afshar-Sterle, S
Baloyan, D
Hannan, NJ
Buchert, M
Scott, AM
Griffin, MDW
Hollande, F
Parker, MW
Putoczki, TL
Ernst, M
Chand, AL
Issue Year: 2019
Publisher WILEY
Series EMBO MOLECULAR MEDICINE:
Abstract Activation of the heterotrimeric energy-sensing kinase AMP-activated protein kinase (AMPK) has been reported to improve experimental diabetic kidney disease. We examined the effect of type 1 diabetes in wild-type (WT) mice and mice lacking the beta 1 subunit of AMPK (AMPK beta 1(-/-) mice), which have reduced AMPK activity in kidneys and other organs. Diabetes was induced using streptozotocin (STZ) and the animals followed up for 4 weeks. Hyperglycaemia was more severe in diabetic AMPK beta 1(-/-) mice, despite the absence of any difference in serum levels of insulin, adiponectin and leptin. There was no change in AMPK activity in the kidneys of diabetic WT mice by AMPK activity assay, or phosphorylation of either the alpha T172 activation site on the alpha catalytic subunit of AMPK or the AMPK-specific phosphosite S79 on acetyl CoA carboxylase 1 (ACC1). Phosphorylation of the inhibitory alpha S485 site on the alpha subunit of AMPK was significantly increased in the WT diabetic mice compared to non-diabetic controls. Despite increased plasma glucose levels in the diabetic AMPK beta 1(-/-) mice, there were fewer myofibroblasts in the kidneys compared to diabetic WT mice, as evidenced by reduced alpha-smooth muscle actin (alpha-SMA) protein by Western blot, mRNA by qRT-PCR and fewer alpha-SMA-positive cells by immunohistochemical staining. Albuminuria was also reduced in the AMPK beta 1(-/-) mice. In contrast to previous studies, therefore, myofibroblasts were reduced in the kidneys of AMPK beta 1(-/-) diabetic mice compared to diabetic WT mice, despite increased circulating glucose, suggesting that AMPK can worsen renal fibrosis in type 1 diabetes.
URI: https://publications.svi.edu.au/publications/7878
Other Identifiers 10.15252/emmm.201809539
Publication type Article