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      Kidney Expression of RhoA, TGF-β1, and Fibronectin in Human IgA Nephropathy

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          Background: The Rho/transforming growth factor-β (TGF-β) system plays a crucial role in the progression of renal damage due to stimulation of extracellular matrix molecule deposition. In fact, the in vitro TGF-β-mediated production of fibronectin, one of the major TGF-β-regulated extracellular components, has recently been correlated with Rho protein signalling molecules. Although a close relationship between increased renal tissue levels of TGF-β1 and fibronectin has been reported in IgA nephropathy, no data are available on renal tissue expression of Rho proteins. Methods: This study was designed to assess in IgA nephropathy patients the kidney tissue immunohistochemical expression of RhoA, TGF-β1, and fibronectin, and the rate of immunoreactivity for each antigen by image analysis. Results: An increase in RhoA, TGF-β1, and fibronectin expression was detected in tubulointerstitium and in glomeruli of IgA nephropathy compared to normal kidneys; in particular, RhoA was found also in proximal tubules, unlike control kidneys and mainly at the cell boundary level, which is in keeping with its activated form. The image analysis confirmed that the kidney tissue levels of RhoA, TGF-β1, and fibronectin were significantly enhanced in the patients. Conclusion: This study suggests that RhoA may represent a key molecule in the signalling transduction pathway of profibrotic signals in IgA nephropathy.

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          Most cited references 22

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          An essential role for Rac in Ras transformation.

          The GTPase Rac1 is a key component in the reorganization of the actin cytoskeleton that is induced by growth factors or oncogenic Ras1. Here we investigate the role of Rac1 in cell transformation and show that Rat1 fibroblasts expressing activated Val-12 Rac1 (Rac1 with valine at residue 12) display all the hallmarks of malignant transformation. In a focus-forming assay in NIH3T3 fibroblasts to measure the efficiency of transformation, we found that dominant-negative Asn-17 Rac1 inhibited focus formation by oncogenic Ras, but not by RafCAAX, a Raf kinase targeted to the plasma membrane by virtue of the addition of a carboxyterminal localization signal from K-Ras. This indicates that Rac is essential for transformation by Ras. In addition, Val-12 Rac1 synergizes strongly with RafCAAX in focus-formation assays, indicating that oncogenic Ras drives both the Rac and MAP-kinase pathways, which cooperate to cause transformation.
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            Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha.

            The Rho small G protein family members regulate various actin cytoskeleton-dependent cell functions. The Rho GDI (GDP dissociation inhibitor) family, consisting of Rho GDIalpha, -beta, and -gamma, is a regulator that keeps the Rho family members in the cytosol as the GDP-bound inactive form and translocates the GDP-bound form from the membranes to the cytosol after the GTP-bound form accomplishes their functions. Rho GDIalpha is ubiquitously expressed in mouse tissues and shows GDI activity on all the Rho family members in vitro. We have generated mice lacking Rho GDIalpha by homologous recombination to clarify its in vivo function. Rho GDIalpha -/- mice showed several abnormal phenotypes. Firstly, Rho GDIalpha -/- mice were initially viable but developed massive proteinuria mimicking nephrotic syndrome, leading to death due to renal failure within a year. Histologically, degeneration of tubular epithelial cells and dilatation of distal and collecting tubules were readily detected in the kidneys. Secondly, Rho GDIalpha -/- male mice were infertile and showed impaired spermatogenesis with vacuolar degeneration of seminiferous tubules in their testes. Thirdly, Rho GDIalpha -/- embryos derived from Rho GDIalpha -/- female mice were defective in the postimplantation development. In addition, these morphological and functional abnormalities showed age-dependent progression. These results suggest that the signaling pathways of the Rho family members regulated by Rho GDIalpha play important roles in maintaining the structure and physiological function of at least kidneys and reproductive systems in adult mice.
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              Expression of transforming growth factor-β isoforms in human glomerular diseases


                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                September 2005
                30 May 2005
                : 101
                : 1
                : e16-e23
                Departments of aHuman Morphology and Applied Biology, Histology and Medical Embryology Section, bInternal Medicine, Nephrology Unit, and cEndocrinology and Metabolism, University of Pisa, Pisa, Italy
                86035 Nephron Exp Nephrol 2005;101:e16–e23
                © 2005 S. Karger AG, Basel

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                Figures: 5, References: 44, Pages: 1
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