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Biomedical subjects

Giovanna Giannico

Publications and source records attributed to Giovanna Giannico.

5 recordsLinked to original sources
PubMed2006

Glibenclamide prevents increased extracellular matrix formation induced by high glucose concentration in mesangial cells.

Other than stimulation of cell contractility, little is known about the potential metabolic effects induced by sulfonylureas, independently of insulin action. Previous studies from our laboratory demonstrated complete abrogation of glomerulosclerosis in an experimental model of type 1 diabetes chronically (9 mo) treated with low-dose sulfonylureas (Biederman JI, Vera E, Pankhaniya R, Hassett C, Giannico G, Yee J, Cortes P. Kidney Int 67: 554-565, 2005). Therefore, the effects of glibenclamide (Glib) on net collagen I, collagen IV, and fibronectin medium net secretion and cell layer collagen I deposition were investigated in mesangial cells continuously exposed to 25 mM glucose for 8 wk and treated with predetermined increasing concentrations of Glib for the same period. Clinically relevant concentrations (0.01 microM) of Glib fully suppressed the high glucose-enhanced accumulation of collagen I, collagen IV, and fibronectin in the medium and inhibited collagen I deposition in the cell layer. These effects occurred while transforming growth factor (TGF)-beta1 medium concentration remained elevated and glucose uptake was increased to levels above those in 25 mM glucose-incubated cultures. The decreased collagen I accumulation occurred simultaneously with enhanced collagen I mRNA expression in concert with marked suppression of plasminogen inhibitor type-1 (PAI-1) mRNA and protein expression. This strongly suggests an accelerated matrix turnover favoring breakdown. Glib-induced effects demonstrated a biphasic pattern, being absent or reversed in cells treated with higher Glib concentrations (0.1 or 1 microM). Therefore, chronic Glib treatment at low concentrations markedly diminishes the high glucose-induced enhanced accumulation of extracellular matrix components by suppression of steady-state PAI-1 transcriptional activity. These results and those previously reported in vivo suggest that long-term Glib treatment may prevent glomerulosclerosis in insulin-deficient diabetes.

Actins↗
PubMed2005

Distinct epitopes for anti-glomerular basement membrane alport alloantibodies and goodpasture autoantibodies within the noncollagenous domain of alpha3(IV) collagen: a janus-faced antigen.

Alport posttransplantation anti-glomerular basement membrane (GBM) nephritis is mediated by alloantibodies against the noncollagenous (NC1) domains of the alpha3alpha4alpha5(IV) collagen network, which is present in the GBM of the allograft but absent from Alport kidneys. The specificity of kidney-bound anti-GBM alloantibodies from a patient who had autosomal recessive Alport syndrome (ARAS) and developed posttransplantation nephritis was compared with that of Goodpasture autoantibodies from patients with autoimmune anti-GBM disease. Allograft-eluted alloantibodies reacted specifically with alpha3alpha4alpha5 NC1 hexamers, targeting their alpha3NC1 and alpha4NC1 subunits, and recognized a noncontiguous alloepitope formed jointly by the E(A) and E(B) regions of alpha3NC1 domain. In contrast, human Goodpasture autoantibodies recognized the separate E(A) and E(B) autoepitopes of alpha3NC1 but not the composite alloepitope. Molecular modeling of alpha3NC1 revealed that the alloepitope is more accessible within the NC1 hexamers than the partially sequestered Goodpasture autoepitopes. Overall, the specificity of alloantibodies indicated a selective lack of immune tolerance toward the alpha3 and alpha4(IV) collagen chains not expressed in patients with ARAS. Using COL4A3 knockout mice, a model of ARAS, it was shown further that acid-dissociated rather than native alpha3alpha4alpha5 NC1 hexamers elicited murine anti-GBM antibodies most closely resembling human ARAS alloantibodies. In contrast, alpha3NC1 monomers elicited Goodpasture-like murine antibodies, targeting the E(A) and E(B) autoepitopes. Thus, the identity of alpha3NC1 epitopes targeted by anti-GBM antibodies is strongly influenced by the molecular organization of the immunogen. These findings suggest that different isoforms of alpha3(IV) collagen may be implicated in the pathogenesis of ARAS posttransplantation anti-GBM nephritis and Goodpasture disease.

Adult↗
PubMed2005

Effects of sulfonylureas, alpha-endosulfine counterparts, on glomerulosclerosis in type 1 and type 2 models of diabetes.

BACKGROUND: Previously, we showed the expression of a unique sulfonylurea receptor (SUR) and its putative endogenous ligand, alpha-endosulfine, in mesangial cells and isolated glomeruli. Further, this ligand was up-regulated by high glucose concentration. To investigate the possible role of alpha-endosulfine up-regulation in diabetes, we administered sulfonylureas, the exogenous ligands of SUR, to diabetic animals. METHODS: In streptozotocin-induced, insulin-deficient, diabetic rats, glomerulosclerosis, albuminuria, glomerular expression of fibronectin mRNA, and glomerular filtration rate (GFR) were studied for various periods up to 36 weeks. Several rat groups received either glibenclamide or tolazamide during the entire study period. Also, glomerulosclerosis and albuminuria were determined in insulin-resistant db/db mice, at 26 weeks of treatment with tolazamide. RESULTS: Sulfonylureas did not improve hyperglycemia or reduce glycosylated hemoglobin levels. In insulin-deficient diabetic rats, sulfonylureas significantly decreased the degree of glomerulosclerosis and completely reversed the enhanced albumin excretion. Also, glibenclamide reduced diabetes-induced glomerular overexpression of fibronectin mRNA. Because glibenclamide may improve the afferent arteriolar dilatation of diabetes, thereby reducing glomerular hyperfiltration, its effect on GFR was determined. Glibenclamide did not alter glomerular hyperfiltration or renal hypertrophy, regardless of the intensity of hyperglycemia. Finally, in insulin-resistant mice, tolazamide did not alter the extent of diabetic glomerulosclerosis or increased albuminuria. CONCLUSION: Long-term treatment with sulfonylureas completely prevents glomerular injury in insulin-deficient diabetes in rats. However, this protective effect is not demonstrable in an insulin-resistant model of the disease. We postulate that mesangial alpha-endosulfine up-regulation in the hyperglycemic milieu of insulin-deficient diabetes may retard glomerular extracellular matrix formation and mesangial expansion.

Animals↗
PubMed2004

Regulation of the membrane-localized prostaglandin E synthases mPGES-1 and mPGES-2 in cardiac myocytes and fibroblasts.

The proinflammatory mediator cyclooxygenase (COX)-2 and its product PGE(2) are induced in the ischemic heart, contributing to inflammatory cell infiltration, fibroblast proliferation, and cardiac hypertrophy. PGE(2) synthesis coupled to COX-2 involves two membrane-localized PGE synthases, mPGES-1 and mPGES-2; however, it is not clear how these synthases are regulated in cardiac myocytes and fibroblasts. To study this, we used primary cultures of neonatal ventricular myocytes (VM) and fibroblasts (VF) treated with IL-1beta for 24 h. To test for involvement of MAPKs in IL-1beta regulation of mPGES-1 and-2, cells were pretreated with the pharmacological inhibitors of p42/44 MAPK, p38 MAPK, and c-Jun kinase (JNK). mRNA was analyzed by RT-PCR. Protein was analyzed by densitometry of Western blots. mPGES-1 was undetectable in untreated VF but induced by IL-1beta; inhibition of either p42/44 MAPK or JNK, but not p38 MAPK, was almost completely inhibitory. In VM, inhibition of the three MAPKs reduced IL-1beta-stimulated mPGES-1 protein by 70-90%. mPGES-2 was constitutively synthesized in both VM and VF and was not regulated by IL-1beta or MAPKs. Confocal microscopy revealed colocalization of both mPGES-1 and mPGES-2 with COX-2 in the perinuclear area of both VF and VM. Finally, PGE(2) production was higher in VM than VF. Our data show that 1) mPGES-1 is induced in both VF and VM, 2) regulation of mPGES-1 by MAPK family members is different in the two cell types, 3) mPGES-2 is constitutively synthesized in both VM and VF and is not regulated, and 4) mPGES-1 and mPGES-2 are colocalized with COX-2 in both cells. Thus differences in activity of mPGES-1 and COX-2 or coupling of COX-2 with mPGES-1 may contribute to differences in PGE(2) production by myocytes and fibroblasts.

Animals↗