title: Role of the JAK2/STAT pathway and losartan in human glomerular mesangial cell senescence.
abstract: Glomerular mesangial cells (GMCs) have a finite cell lifespan and eventually enter irreversible growth arrest known as cellular senescence. The functional changes associated with cellular senescence are thought to contribute to human aging and age-related kidney disorders, such as chronic kidney disease. Angiotensin II (AngII), a principal effector of the renin-angiotensin system (RAS), is known to promote aging and cellular senescence. The cellular and molecular mechanisms responsible for the senescence of GMCs remain largely undefined. The JAK2/STAT pathway plays a pivotal role in transmitting cytokine signals. To date, little is known regarding the relationship between AngII or STAT protein and aging human GMCs. Therefore, this study was designed to determine the effects of AngII and the JAK2/STAT pathway on the process of GMC aging. We observed the functions of the AngII receptor blocker losartan and the JAK2 blocker AG490 in delaying GMC aging. Cells were assigned to a control group, an AngII-induced group, a losartan + AngII-stimulated group and an AG490 + AngII-treated group. AngII promoted growth arrest with phenotypic characteristics of cell senescence, such as enlarged cell morphology, polymorphic nuclei and vacuolization, increased staining for senescence-associated β-galactosidase, and depressed cell proliferation. The JAK2/STAT1/3 pathway is drastically activated in AngII-induced senescence cells. Compared to the AngII-induced group, in the cells treated with losartan and AG490, the characteristics of cell senescence were ameliorated, and the expression of STAT1, STAT3, pSTAT1 and pSTAT3 was decreased. Our results suggest that AngII induces human GMC senescence, and that the JAK2/STAT1/3 pathway is involved in this process. By applying losartan and blocking the JAK2/STAT pathway, it may be possible to delay GMC aging.
authors.affiliation: Department of Nephropathy, First Affiliated Hospital of China Medical University, Liaoning 110001, P.R. China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Lining
authors.initials: L
authors.lastname: Wang