PAN-AMPK Activation Improves Renal Function in a Rat Model of Progressive Diabetic Nephropathy.

AMP-Activated Protein Kinase Kinases Aged Animals Benzimidazoles Blood Glucose / metabolism Blood Pressure Cells, Cultured Diabetic Nephropathies / drug therapy Female Glomerular Filtration Rate Humans Hypoglycemic Agents / pharmacology Imidazoles / pharmacology Kidney / drug effects Male Middle Aged Mitochondria / drug effects Protein Kinases / metabolism Pyridines / pharmacology Rats Rats, Zucker Triglycerides / blood

Journal

The Journal of pharmacology and experimental therapeutics
ISSN: 1521-0103
Titre abrégé: J Pharmacol Exp Ther
Pays: United States
ID NLM: 0376362

Informations de publication

Date de publication:
10 2019
Historique:
received: 20 03 2019
accepted: 03 07 2019
pubmed: 14 7 2019
medline: 21 4 2020
entrez: 14 7 2019
Statut: ppublish

Résumé

Metabolic dysregulation and mitochondrial dysfunction are important features of acute and chronic tissue injury across species, and human genetics and preclinical data suggest that the master metabolic regulator 5'-adenosine monophosphate-activated protein kinase (AMPK) may be an effective therapeutic target for chronic kidney disease (CKD). We have recently disclosed a pan-AMPK activator, MK-8722, that was shown to have beneficial effects in preclinical models. In this study we investigated the effects of MK-8722 in a progressive rat model of diabetic nephropathy to determine whether activation of AMPK would be of therapeutic benefit. We found that MK-8722 administration in a therapeutic paradigm is profoundly renoprotective, as demonstrated by a reduction in proteinuria (63% decrease in MK-8722 10 mg/kg per day compared with vehicle group) and a significant improvement in glomerular filtration rate (779 and 430

Identifiants

DOI: 10.1124/jpet.119.258244 PMID: 31300612
pubmed: 31300612
pii: jpet.119.258244
doi: 10.1124/jpet.119.258244
doi:

Substances chimiques

Benzimidazoles 0
Blood Glucose 0
Hypoglycemic Agents 0
Imidazoles 0
MK-8722 0
Pyridines 0
Triglycerides 0
Protein Kinases EC 2.7.-
AMP-Activated Protein Kinase Kinases EC 2.7.11.3

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

45-55

Informations de copyright

Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.

Auteurs

Xiaoyan Zhou (X)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey xiaoyan_zhou@merck.com.

Eric S Muise (ES)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey.

Robin Haimbach (R)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey.

Iyassu K Sebhat (IK)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey.

Yonghua Zhu (Y)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey.

Franklin Liu (F)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey.

Sandra C Souza (SC)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey.

Yanqing Kan (Y)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey.

Shirly Pinto (S)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey.

David E Kelley (DE)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey.

Maarten Hoek (M)

Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey mhoek@mazetx.com.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › AMP-activated protein kinase kinases › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Eucaryotes › Animaux › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzimidazoles › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Glucides › Sucres › Oses › Hexose › Glucose › Glycémie › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Phénomènes physiologiques respiratoires et circulatoires › Phénomènes physiologiques cardiovasculaires › Hémodynamique › Pression sanguine › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Cellules › Cellules cultivées › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Maladies endocriniennes › Diabète › Complications du diabète › Néphropathies diabétiques › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Phénomènes physiologiques des appareils urinaire et reproducteur › Phénomènes physiologiques des voies urinaires › Débit de filtration glomérulaire › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hypoglycémiants › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Imidazoles › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Appareil urogénital › Voies urinaires › Rein › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Phosphotransferases (Alcohol Group Acceptor) › Protein kinases › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Souches mutantes de rat › Rat Zucker › PAN-AMPK Activation Improves Renal Function in...
questionsmedicales.fr › Lipides › Glycérides › Triglycéride › PAN-AMPK Activation Improves Renal Function in...