Renal protective effects of empagliflozin via inhibition of EMT and aberrant glycolysis in proximal tubules.

JCI Insight
Jinpeng LiDaisuke Koya

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibitors are beneficial in halting diabetic kidney disease; however, the complete mechanisms have not yet been elucidated. The epithelial-mesenchymal transition (EMT) is associated with the suppression of sirtuin 3 (Sirt3) and aberrant glycolysis. Here, we hypothesized that the SGLT2 inhibitor empagliflozin restores normal kidney histology and function in association with the inhibition of aberrant glycolysis in diabetic kidneys. CD-1 mice with streptozotocin-induced diabetes displayed kidney fibrosis that was associated with the EMT at 4 months after diabetes induction. Empagliflozin intervention for 1 month restored all pathological changes; however, adjustment of blood glucose by insulin did not. Empagliflozin normalized the suppressed Sirt3 levels and aberrant glycolysis that was characterized by HIF-1α accumulation, hexokinase 2 induction, and pyruvate kinase isozyme M2 dimer formation in diabetic kidneys. Empagliflozin also suppressed the accumulation of glycolysis byproducts in diabetic kidneys. Another SGLT2 inhibitor, canagliflozin, demonstrated similar in vivo effects. High-glucose media induced the EMT, which was associated with Sirt3 suppression and aberrant glycolysis induct...Continue Reading

References

Apr 1, 1986·Physiological Reviews·G Wirthensohn, W G Guder
Sep 22, 2001·The New England Journal of Medicine·B M BrennerUNKNOWN RENAAL Study Investigators
Nov 18, 2005·Journal of the American Society of Nephrology : JASN·Masaomi Nangaku
Nov 27, 2007·The Journal of Clinical Investigation·Debra F HigginsVolker H Haase
Jul 31, 2009·Nature·Toren FinkelRaul Mostoslavsky
Aug 5, 2009·The Journal of Clinical Investigation·Nagalingam R SundaresanMahesh P Gupta
Jun 16, 2010·Diabetic Medicine : a Journal of the British Diabetic Association·J E Gerich
Oct 23, 2010·Molecular Cell·Amar J MajmundarM Celeste Simon
Mar 15, 2011·Cancer Cell·Lydia W S FinleyMarcia C Haigis
Aug 16, 2011·Clinical & Experimental Metastasis·Joseph L SottnikDouglas H Thamm
May 9, 2012·The EMBO Journal·Samantha N GreerMichael Ohh
Jan 3, 2013·Cancer Science·Tomoyoshi Soga
Feb 8, 2013·Frontiers in Endocrinology·Keizo KanasakiDaisuke Koya
Aug 21, 2013·Indian Journal of Endocrinology and Metabolism·Resham Raj Poudel
Dec 17, 2014·American Journal of Physiology. Renal Physiology·Jinu KimBabu J Padanilam
Sep 18, 2015·The New England Journal of Medicine·Bernard ZinmanUNKNOWN EMPA-REG OUTCOME Investigators
Dec 17, 2015·Molecular and Cellular Biology·Nagalingam R SundaresanMahesh P Gupta
Jan 15, 2016·American Journal of Physiology. Renal Physiology·Takashi HatoTimothy A Sutton
Jun 15, 2016·The New England Journal of Medicine·Christoph WannerUNKNOWN EMPA-REG OUTCOME Investigators
Jul 6, 2016·Oxidative Medicine and Cellular Longevity·Raffaele PalmirottaFranco Silvestris
Feb 24, 2017·American Journal of Physiology. Renal Physiology·Hao DingJunwei Yang
Mar 1, 2017·Journal of Cellular and Molecular Medicine·Hengqiang ZhaoTao Yin
Apr 1, 2018·Seminars in Nephrology·Guanshi ZhangKumar Sharma
Sep 27, 2018·Cell Death & Disease·Swayam Prakash SrivastavaDaisuke Koya
Nov 16, 2018·Science Translational Medicine·Claudio R ScafoglioDavid B Shackelford
Apr 17, 2019·The New England Journal of Medicine·Vlado PerkovicUNKNOWN CREDENCE Trial Investigators

❮ Previous
Next ❯

Citations

Jun 6, 2020·Cells·Swayam Prakash Srivastava, Julie E Goodwin
May 1, 2020·British Journal of Pharmacology·Swayam Prakash SrivastavaDaisuke Koya
Aug 19, 2020·The Journal of Clinical Investigation·Jenny E Gunton
Jan 29, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Jie ChenJunwei Liu
Dec 29, 2020·Frontiers in Pharmacology·Swayam Prakash SrivastavaJulie E Goodwin
Feb 26, 2021·The FEBS Journal·Liad HindenGil Leibowitz
Mar 27, 2021·Current Opinion in Nephrology and Hypertension·Caitlyn VlasschaertSamuel A Silver
May 14, 2021·IScience·Swayam Prakash SrivastavaDaisuke Koya
Oct 6, 2020·JACC. Basic to Translational Science·Milton Packer
Jul 27, 2021·Frontiers in Pharmacology·Swayam Prakash SrivastavaJulie E Goodwin
Jul 17, 2021·Trends in Endocrinology and Metabolism : TEM·Mark LambieVictor Zammit
Jul 27, 2021·Journal of the American Heart Association·Swayam Prakash SrivastavaJulie Goodwin
Aug 10, 2021·Frontiers in Medicine·Jing XuDaisuke Koya
Aug 29, 2021·Pharmaceuticals·Swayam Prakash SrivastavaJulie E Goodwin
Aug 29, 2021·Nefrología : publicación oficial de la Sociedad Española Nefrologia·Usama Abdel Azim Sharaf El DinDina Ossama Abdulazim
Oct 14, 2021·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Kouichi TamuraTakahiro Yamaji

❮ Previous
Next ❯

Methods Mentioned

BETA
transfection
electron microscopy
SMA
fluorescence microscopy
transmission electron microscopy
ELISA

Software Mentioned

ImageJ
GraphPad Prism

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.