title: High glucose level unmasks a genetic predisposition to enhanced extracellular matrix production in mesangial cells from the Milan normotensive strain.
abstract: A growing body of evidence indicates that the individual genetic background plays a role in the pathogenesis of diabetic glomerular disease by either favoring or protecting against injury produced by hyperglycemia. Two genetically related rat strains, the Milan normotensive strain (MNS) and the Milan hypertensive strain (MHS) display different susceptibilities to develop glomerulosclerosis with age. Glomerular sclerosing lesions occur in the MNS rats, which remain normotensive throughout their entire life-span, but not in the MHS rats, despite the presence of arterial hypertension. Previous studies have reported that extracellular matrix production and cell proliferation increased with donor-aging in mesangial cells isolated from MNS rats, but not in those from MHS rats, thus suggesting the existence of an inherited defect in the regulation of cell and matrix turnover, which translates into an abnormal response to growth-promoting stimuli favoring the development of glomerulosclerosis. In the study presented here, it was hypothesized that, in addition to donor-aging, other independent risk factors for the development of glomerular disease, such as metabolic injury by hyperglycemia, would be able to trigger and/or precipitate the occurrence of these changes in mesangial cells from the susceptible normotensive strain, but not in those from the protected hypertensive strain. To test this hypothesis, mesangial cells obtained from these rat strains (before the onset of either glomerulosclerosis or hypertension) were used to assess the effects of prolonged (4 wk) exposure to high (30 mmol/L) versus normal (5.5 mmol/L) glucose concentrations on extracellular matrix and cytokine production and cell proliferation. The accumulation and/or gene expression of the matrix components fibronectin, laminin, and collagen IV, and of the cytokines insulin-like growth factor-I (IGF-I) and transforming growth factor-beta (TGF-beta) did not change under normal glucose and increased progressively in response to high glucose in both MNS and MHS cells. These increases, with the exception of the increment in TGF-beta gene expression, were significantly more pronounced in MNS cells than in MHS cells. In contrast, the proliferative response to serum was not affected by high glucose, but increased in MNS cells, and decreased, although not significantly, in MHS cells during the 4-wk period, thus mimicking the changes previously observed in these rat strains as a function of age. These results indicate that high glucose unmasks a genetic tendency to produce increasing amounts of extracellular matrix, not yet evident under normal glucose conditions, and suggest that a genetically determined propensity of mesangial cells to hyperrespond to chronic hyperglycemia may be implicated in the pathogenesis of diabetic glomerular disease.
authors.affiliation: Dipartimento di Medicina Sperimentale (Patologia Generale I e Statistica Medica e Biometria), University of Rome, La Sapienza, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Pugliese
authors.forename: F
authors.initials: F
authors.lastname: Pricci
authors.forename: P
authors.initials: P
authors.lastname: Menè
authors.forename: G
authors.initials: G
authors.lastname: Romeo
authors.forename: I
authors.initials: I
authors.lastname: Nofroni
authors.forename: S
authors.initials: S
authors.lastname: Giannini
authors.forename: B
authors.initials: B
authors.lastname: Cresci
authors.forename: G
authors.initials: G
authors.lastname: Galli
authors.forename: C M
authors.initials: CM
authors.lastname: Rotella
authors.forename: U
authors.initials: U
authors.lastname: Di Mario
authors.forename: F
authors.initials: F
authors.lastname: Pugliese
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001794:Blood Pressure; D002455:Cell Division; D005109:Extracellular Matrix / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics; D006973:Hypertension / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011922:Rats, Mutant Strains; D012016:Reference Values; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D001786:Blood Glucose; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I