Inhibition of PAI-1 attenuates perirenal fat inflammation and the associated nephropathy in high-fat diet-induced obese mice.

Autor:	Liu Y; Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, People's Republic of China.; State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology), Taipa, Macau, People's Republic of China.; Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan , People's Republic of China.; Laboratory for Cardiovascular Pharmacology of the Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan , People's Republic of China., Wang L; Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan , People's Republic of China.; Laboratory for Cardiovascular Pharmacology of the Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan , People's Republic of China., Luo M; Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan , People's Republic of China.; Laboratory for Cardiovascular Pharmacology of the Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan , People's Republic of China., Chen N; Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan , People's Republic of China.; Laboratory for Cardiovascular Pharmacology of the Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan , People's Republic of China., Deng X; Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan , People's Republic of China.; Laboratory for Cardiovascular Pharmacology of the Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan , People's Republic of China., He J; Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan , People's Republic of China.; Laboratory for Cardiovascular Pharmacology of the Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan , People's Republic of China., Zhang L; Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan , People's Republic of China.; Laboratory for Cardiovascular Pharmacology of the Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan , People's Republic of China., Luo P; Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, People's Republic of China.; State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology), Taipa, Macau, People's Republic of China., Wu J; Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, People's Republic of China.; State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology), Taipa, Macau, People's Republic of China.; Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan , People's Republic of China.; Laboratory for Cardiovascular Pharmacology of the Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan , People's Republic of China.; Department of Medicine and Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine and Research Service , Columbia, Missouri.; Harry S. Truman Memorial Veterans Hospital , Columbia, Missouri.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2019 Feb 01; Vol. 316 (2), pp. E260-E267. Date of Electronic Publication: 2018 Dec 11.
DOI:	10.1152/ajpendo.00387.2018
Abstrakt:	Plasminogen activator inhibitor-1 (PAI-1) is increasingly recognized as a mediator in extracellular matrix (ECM) accumulation in diabetic nephropathy. Previous studies have implicated PAI-1 in adipose tissue (AT) expansion, while also contributing to insulin resistance. As inflammation is also known to occur in perirenal AT during obesity, we hypothesized that in a high-fat diet (HFD)-induced obese mouse model, PAI-1 contributes to macrophage-mediated inflammation and diabetic nephropathy. The HFD mice showed increased expression of PAI-1 in perirenal fat and also displayed increased fat weight and macrophage numbers. We found that the macrophage polarization, proinflammatory macrophage-M1-phenotype, including CD11c, IL-6, and monocyte chemoattractant protein-1, were increased by an HFD and decreased by either the genetic depletion of PAI-1 or treatment with the PAI-1 inhibitor, PAI-039. Similarly, an enhanced anti-inflammatory M2-phenotype, including CD206 and IL-10, was accompanied by either the genetic deletion of PAI-1 or PAI-039 treatment. Furthermore, the inhibition of PAI-1 reduced HFD-induced renal histological lesions and abated profibrotic/extracellular-matrix protein. Collectively, our findings provide support that PAI-1 contributes to the development of inflammation in perirenal fat and correlates with the development of diabetic nephropathy in HFD-induced obesity.
Databáze:	MEDLINE
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