title: The glomerulosclerosis of aging in females: contribution of the proinflammatory mesangial cell phenotype to macrophage infiltration.
abstract: Age-associated renal changes may be an important cause of renal failure. We recently found that aged female B6 mice developed progressive glomerular lesions. This was associated with macrophage infiltration, a frequent finding in glomerulosclerosis. We used these mice as a model for studying the mechanisms of glomerular aging. We compared the gene expression profile of intact glomeruli from late postmenopausal (28-month-old) mice to that of intact glomeruli from premenopausal (5-month-old) mice. We found that inflammation-related genes, especially those expressed by activated macrophages, were up-regulated in the glomeruli of 28-month-old mice, a result correlating with the histological observation of glomerular macrophage infiltration. The mechanism for macrophage recruitment could have been stable phenotypic changes in mesangial cells because we found that mesangial cells isolated from 28-month-old mice expressed higher levels of RANTES and VCAM-1 than cells from 5-month-old mice. The elevated serum tumor necrosis factor (TNF)-alpha levels present in aged mice may contribute to increased RANTES and VCAM-1 expression in mesangial cells. Furthermore, cells from 28-month-old mice were more sensitive to TNF-alpha-induced RANTES and VCAM-1 up-regulation. The effect of TNF-alpha on RANTES expression was mediated by TNF receptor 1. Interestingly, mesangial cells isolated from 28-month-old mice had increased nuclear factor-kappaB transcriptional activity. Inhibition of nuclear factor-kappaB activity decreased baseline as well as TNF-alpha-induced RANTES and VCAM-1 expression in mesangial cells isolated from 28-month-old mice. Thus, phenotypic changes in mesangial cells may predispose them to inflammatory stimuli, such as TNF-alpha, which would contribute to glomerular macrophage infiltration and inflammatory lesions in aging.
authors.affiliation: Vascular Biology Institute, University of Miami School of Medicine, Rosenstiel Medical Science Building, Room 1023A, 1600 NW 10th Ave., Miami, FL 33136, USA. fzheng@med.miami.edu
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: Cheng
authors.forename: Anna-Rita
authors.initials: AR
authors.lastname: Plati
authors.forename: Shui Qin
authors.initials: SQ
authors.lastname: Ye
authors.forename: Mariana
authors.initials: M
authors.lastname: Berho
authors.forename: Anita
authors.initials: A
authors.lastname: Banerjee
authors.forename: Mylene
authors.initials: M
authors.lastname: Potier
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Jaimes
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: You-Fei
authors.initials: YF
authors.lastname: Guan
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Hao
authors.forename: Liliane J
authors.initials: LJ
authors.lastname: Striker
authors.forename: Gary E
authors.initials: GE
authors.lastname: Striker
mesh_terms: D000375:Aging; D000818:Animals; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005920:Glomerular Mesangium / Q000473:pathology*; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D018946:Chemokine CCL5; D016328:NF-kappa B; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D012313:RNA