Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging

Abstract

Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-II -arginine-ureahydrolase, is highly expressed in pancreas. However, its role in regulation of pancreatic β-cell function is not known. Here we show that female (not male) mice deficient in Arg-II (Arg-II) are protected from age-associated glucose intolerance and reveal greater glucose induced-insulin release, larger islet size and β-cell mass, and more proliferative and less apoptotic β-cells compared with the age-matched wild-type (WT) controls. Moreover, Arg-II is mainly expressed in acinar cells and is upregulated with aging, which enhances p38 mitogen-activated protein kinase (p38 MAPK) activation and release of tumor necrosis factor-α (TNF-α). Accordingly, conditioned medium of isolated acinar cells from old WT (not Arg-II) mice contains higher TNF-α levels than the young mice and stimulates β-cell apoptosis and dysfunction, which are prevented by a neutralizing anti-TNF-α antibody. In acinar cells, our study demonstrates an age-associated Arg-II upregulation, which promotes TNF-α release through p38 MAPK leading to β-cell apoptosis, insufficient insulin secretion, and glucose intolerance in female rather than male mice.

Arginase-II Deficiency Extends Lifespan in Mice

“…Regulation of lifespan of an organism is complex, involving multiple organs and cells. The age-associated increase in Arg-II expression was also observed previously in other tissues or organs, such as blood vessels and pancreas (Steppan et al, 2006 ; Khan et al, 2012 ; Yepuri et al, 2012 ; Xiong et al, 2013 , 2017 ). These studies demonstrate that Arg-II plays a causative role in cellular senescence and in the organ functional decline.…”

“…These studies demonstrate that Arg-II plays a causative role in cellular senescence and in the organ functional decline. Previous studies including our own demonstrate beneficial effects of Arg-II deficiency in protection against development of cardiovascular diseases, insulin resistance, and diabetic complications (Ming et al, 2012 ; Yepuri et al, 2012 ; Huang et al, 2016 ; Xiong et al, 2017 ), which could contribute to the lifespan extension by Arg-II deficiency. It remains a great challenge to investigate which organ or cell and to which degree of the organ or cell contribute to the extension of lifespan.…”

“…This function of Arg-II is mediated through interaction with mTOR/S6K1 and p66 Shc in vascular cells, which contributes to atherosclerotic cardiovascular diseases and cardiovascular aging. Indeed, genetic knock-down or knock-out of Arg-II in cells or mice (Arg-II −/− ) demonstrates beneficial effects on the prevention of atherosclerosis, vascular aging, and obesity- and age-associated glucose intolerance (Ming et al, 2012 ; Yepuri et al, 2012 ; Wu et al, 2015 ; Xiong et al, 2017 ). These beneficial effects of Arg-II deficiency on various cellular and organ functions prompted us to hypothesize that Arg-II deficiency could modulate lifespan in mice.…”

Ameliorative effect of urolithin A ond-gal-induced liver and kidney damage in aging miceviaits antioxidative, anti-inflammatory and antiapoptotic properties

“…34,35 The Bcl-2 protein is a key factor in the inhibition of apoptosis; it is a known factor in cell aging, and its overexpression can effectively prevent the apoptosis induced by hydrogen peroxide, free radicals and microbial contamination. 36 On the other hand, the main function of Bax is to accelerate apoptosis and, together with Bcl-2, regulate cell apoptosis. However, the core molecule in apoptosis is cleaved caspase-3 (a cysteine protease), which is known to be mainly in charge of the execution of apoptosis.…”

Arginase-II activates mTORC1 through myosin-1b in vascular cell senescence and apoptosis

“…The mice were maintained in conventional conditions: 23 °C, 12-h light-dark cycle and fed a normal chow and had free access to tap water. Young (5–7 months) and old (22–24 months) mice were sacrificed as previously described 32 . Aortas was isolated and snap-frozen in liquid nitrogen and kept at −80 °C until processed.…”