Metformin attenuates albumin-induced alterations in renal tubular cells in vitro.
Proteinuria (albuminuria) plays a crucial role in the etiology of chronic kidney disease (CKD) via alteration of multiple signaling pathways and cellular process in renal cells. The objectives of this study are to investigate the effects of activation of the energy-sensing molecule AMP-activated kinase (AMPK) in renal cells using metformin on endoplasmic reticulum (ER) stress, AKT, mTOR, epithelial-to-mesenchymal transition (EMT), autophagy, and apoptosis that are thought to mediate renal cell injury during proteinuria, and to dissect the AMPK- and non-AMPK mediated effects of metformin using an in vitro model of albumin-induced renal cell injury. Rat renal proximal tubular (NRK-52E) cells were exposed to 10 and 15 mg/ml of albumin for 72 h in the presence of 1 mM Metformin and/or 0.5 µM compound C, and assessed for alterations in the aforementioned pathways. Metformin treatment restored AMPK phosphorylation and augmented autophagy in renal cells exposed to albumin. In addition, metformin treatment attenuated the albumin-induced phosphorylation of AKT and the downstream targets of mTOR, and prevented albumin-mediated inductions of EMT marker (α-SMA), pro-apoptotic ER stress marker CHOP, and apoptotic caspases -12 and -3 in renal cells. Blockade of metformin-induced AMPK activation with compound C blunted the ER defense response and autophagy but had no effect on the markers of EMT and apoptosis in our model. Our studies suggest that metformin protects renal cells against proteinuric cytotoxicity via suppression of AKT and mTOR activation, inhibition of EMT and apoptosis, and augmentation of autophagy and ER defense response through AMPK-independent and AMPK-dependent mechanisms, respectively.
['Allouch|Soumaya|S|', 'Munusamy|Shankar|S|http://orcid.org/0000-0002-2023-7705']
D055372:AMP-Activated Protein Kinases D000418:Albumins D000818:Animals D017209:Apoptosis D051017:Apoptosis Regulatory Proteins D001343:Autophagy D002460:Cell Line D059865:Endoplasmic Reticulum Stress D058750:Epithelial-Mesenchymal Transition D007004:Hypoglycemic Agents D007687:Kidney Tubules, Proximal D008687:Metformin D010766:Phosphorylation D047428:Protein Kinase Inhibitors D051057:Proto-Oncogene Proteins c-akt D051381:Rats D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases
metformin albuminuria chronic kidney disease AMPK autophagy ER stress