Your browser doesn't support javascript.
loading
Selective Activation of AMPK ß1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy.
Salatto, Christopher T; Miller, Russell A; Cameron, Kimberly O; Cokorinos, Emily; Reyes, Allan; Ward, Jessica; Calabrese, Matthew F; Kurumbail, Ravi G; Rajamohan, Francis; Kalgutkar, Amit S; Tess, David A; Shavnya, Andre; Genung, Nathan E; Edmonds, David J; Jatkar, Aditi; Maciejewski, Benjamin S; Amaro, Marina; Gandhok, Harmeet; Monetti, Mara; Cialdea, Katherine; Bollinger, Eliza; Kreeger, John M; Coskran, Timothy M; Opsahl, Alan C; Boucher, Germaine G; Birnbaum, Morris J; DaSilva-Jardine, Paul; Rolph, Tim.
Afiliación
  • Salatto CT; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Miller RA; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Cameron KO; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Cokorinos E; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Reyes A; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Ward J; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Calabrese MF; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Kurumbail RG; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Rajamohan F; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Kalgutkar AS; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Tess DA; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Shavnya A; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Genung NE; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Edmonds DJ; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Jatkar A; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Maciejewski BS; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Amaro M; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Gandhok H; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Monetti M; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Cialdea K; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Bollinger E; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Kreeger JM; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Coskran TM; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Opsahl AC; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Boucher GG; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Birnbaum MJ; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • DaSilva-Jardine P; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
  • Rolph T; CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachu
J Pharmacol Exp Ther ; 361(2): 303-311, 2017 05.
Article en En | MEDLINE | ID: mdl-28289077
ABSTRACT
Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the ß1 subunit. After confirming that human and rodent kidney predominately express AMPK ß1, we explore the effects of pharmacological activation of AMPK in the ZSF1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevates the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduces the progression of proteinuria to a greater degree than the current standard of care, angiotensin-converting enzyme inhibitor ramipril. Further analyses of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease.
Asunto(s)
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Activadores de Enzimas / Nefropatías Diabéticas / Proteínas Quinasas Activadas por AMP / Aminopiridinas / Indoles / Riñón Límite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Año: 2017 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Activadores de Enzimas / Nefropatías Diabéticas / Proteínas Quinasas Activadas por AMP / Aminopiridinas / Indoles / Riñón Límite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Año: 2017 Tipo del documento: Article