Effects of heme oxygenase system on inflammation, oxidative stress, insulin signaling and tissue injury in liver, heart, kidney and pancreas in obese, diabetic and hypertensive rats
Mishra, Manish 1980-
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Tissue injury and metabolic dysfunction are salient features of obesity, diabetes, and hypertension. Inflammation and oxidative stress are considered key players behind this altered tissue homeostasis that drastically affect several vital organs including liver, heart, kidney and pancreas resulting in the development of hepatic steatosis, cardiomyopathy, nephropathy, pancreatic insulitis and abnormal glucose metabolism. Despite significant advancement in pharmaceutical interventions, the desired efficacy to manage these conditions is still lacking. In these situations, cytoprotective and functional attributes of the heme oxygenase (HO) system can be used as an alternative management tool. Although, the HO system is cytoprotective, its role in tissue injury and dysfunction in obesity, diabetes, and hypertension is not completely clear. To explore the importance of upregulating HO in these conditions, HO is induced through hemin in the rat models of obesity, diabetes and hypertension. My thesis work show that HO upregulation reduced the inflammation and oxidative stress-induced tissue injury in liver, heart, kidney, and pancreas through reduction of proinflammatory M1 macrophage marker (ED1) expression, cytokines (TNF-α, IL-1β, IL-6), oxidative-markers (8-isoprostane, ET-1) and profibrotic/extracellular matrix proteins (TGF-β, collagen-IV, fibronectin) and enhancement of the anti-inflammatory M2-macrophage markers (ED2, CD206, CD36, CD14), adiponectin and total-antioxidant capacity. HO upregulation improved glucose metabolism through potentiation of insulin signalling components (IRS-1, IRS-2, PI3K, GLUT4), reduced hyperglycemia, and enhanced several markers implicated in pancreatic repair and/or regeneration (c-Kit, Sca-1, Oct3/4, Pax2, β-catenin, Islet-1, Nkx6.1 and GLUT2). Collectively, the data from my thesis suggested the multifaceted cytoprotective mechanisms of the HO system against increasing tissue injury and metabolic dysfunction during obesity, diabetes and hypertension. Thus, HO upregulation through hemin may be part of therapeutic management strategies against tissue injury and metabolic dysfunction in obesity, diabetes and hypertension in the future.
DegreeDoctor of Philosophy (Ph.D.)
CommitteePrasad, Kailash; Lee, Paul; Hiebert, Linda; Ianowski, Juan
Copyright DateOctober 2017
Diabetes, hypertension, obesity, tissue injury, insulin signaling