Pan AMPK Activation Protects Tubules in Rat Ischemic Acute Kidney Injury.

Autor:	Frikke-Schmidt H; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States HFrikkeS@ITS.JNJ.com., Albarazanji K; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Qi J; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Frederick D; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Steffen J; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Kalyana-Sundaram S; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Meng R; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Devine ZH; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Chen T; Preclincial Sciences and Translational Safety, Johnson & Johnson Innovative Medicine, China., Li Q; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Du F; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Ho G; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Liu J; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Riley R; Non-Clinical Safety Pathology, Johnson & Johnson Innovative Medicine, United States., Gonzalez-Villalobos RA; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Camacho RC; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Nawrocki AR; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Pryor M; Therapeutics Discovery, Johnson & Johnson Innovative Medicine, United States., Lee M; Therapeutics Discovery, Johnson & Johnson Innovative Medicine, United States., Wong V; Therapeutics Discovery, Johnson & Johnson Innovative Medicine, United States., Matico R; Therapeutics Discovery, Johnson & Johnson Innovative Medicine, United States., Diaz E; Therapeutics Discovery, Johnson & Johnson Innovative Medicine, United States., Krosky D; Therapeutics Discovery, Johnson & Johnson Innovative Medicine, United States., Wall M; Discovery Chemistry, Johnson & Johnson Innovative Medicine, United States., Gao E; Discovery Chemistry, Johnson & Johnson Innovative Medicine, United States., Shah AA; Discovery Chemistry, Johnson & Johnson Innovative Medicine, United States., Leonard J; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Erion M; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Pocai A; Cardiovascular Metabolism, Retina & Pulmonary Hypertension, Johnson & Johnson Innovative Medicine, United States., Player MR; Discovery Chemistry, Johnson & Johnson Innovative Medicine, United States.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2024 Jun 07. Date of Electronic Publication: 2024 Jun 07.
DOI:	10.1124/jpet.124.002120
Abstrakt:	Acute Kidney Injury (AKI) is characterized by an abrupt decline in kidney function and has been associated with excess risks of death, kidney disease progression, and cardiovascular events. The kidney has a high energetic demand with mitochondrial health being essential to renal function and damaged mitochondria has been reported across AKI subtypes. 5' adenosine monophosphate-activated protein kinase (AMPK) activation preserves cellular energetics through improvement of mitochondrial function and biogenesis when ATP levels are low such as under ischemia-induced AKI. We developed a selective potent small molecule pan AMPK activator, compound 1 , and tested its ability to increase AMPK activity and preserve kidney function during ischemia/reperfusion injury in rats. A single administration of 1 caused sustained activation of AMPK for at least 24 hours, protected against acute tubular necrosis, and reduced clinical markers of tubular injury such as NephroCheck and Fractional Excretion of Sodium (FENa). Reduction in plasma creatinine and increased Glomerular Filtration Rate (GFR) indicated preservation of kidney function. Surprisingly, we observed a strong diuretic effect of AMPK activation associated with natriuresis both with and without AKI. Our findings demonstrate that activation of AMPK leads to protection of tubular function under hypoxic/ischemic conditions which holds promise as a potential novel therapeutic approach for AKI. Significance Statement No approved pharmacological therapies currently exist for acute kidney injury. We developed Compound 1 which dose-dependently activated AMPK in the kidney and protected kidney function and tubules after ischemic renal injury in the rat. This was accompanied by natriuresis in injured as well as uninjured rats.
Databáze:	MEDLINE
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