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Published on: May 10, 2024
Selective Activation of AMPK β1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy
Christopher T Salatto1, Russell A Miller2, Kimberly O Cameron2
1CVMET 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, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut christopher.t.salatto@pfizer.com.
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 β1 subunit. After confirming that human and rodent kidney predominately express AMPK β1, 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.
Insights
New activators of adenosine monophosphate-activated protein kinase (AMPK) show promise for treating diabetic nephropathy. These compounds reduce kidney disease progression by targeting AMPK, offering a potential new therapy for this unmet medical need.
Area of Science:
- Biochemistry
- Nephrology
- Pharmacology
Background:
- Diabetic nephropathy is a leading cause of kidney failure with limited treatment options.
- Reduced adenosine monophosphate-activated protein kinase (AMPK) phosphorylation is linked to kidney dysfunction in renal disease.
- Current therapies for diabetic nephropathy only slow disease progression.
Purpose of the Study:
- To identify and characterize novel small molecule activators of AMPK.
- To investigate the therapeutic potential of selective AMPK activation in a rat model of diabetic nephropathy.
Main Methods:
- Identification of small molecules that selectively activate AMPK heterotrimers containing the β1 subunit.
- Pharmacological administration of AMPK activators to ZSF1 rats with diabetic nephropathy.
- Assessment of AMPK phosphorylation, proteinuria, blood glucose levels, urine biomarkers, and kidney tissue gene expression.
Main Results:
- Novel AMPK activators were identified and confirmed to selectively activate AMPK β1 heterotrimers.
- Chronic administration of these activators increased kidney AMPK phosphorylation without affecting blood glucose.
- AMPK activation significantly reduced proteinuria progression compared to ramipril and modulated pathways involved in kidney injury.
Conclusions:
- Selective activation of AMPK β1 is a promising therapeutic strategy for diabetic nephropathy.
- AMPK activation may mitigate kidney injury by targeting cellular hypertrophy, fibrosis, and oxidative stress.
- Further research is warranted to explore the clinical utility of AMPK activators in kidney disease.
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