Toshio Homma

Vanderbilt University, Нашвилл, Michigan, United States

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Publications (5)24.8 Total impact

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    ABSTRACT: Transforming growth factor (TGF)beta is implicated in the pathogenesis of cyclosporine A (CsA) nephrotoxicity. We examined the efficacy of TGF beta receptor (R)II/immunoglobulin (Ig)G Fc, a soluble chimeric protein consisting of the extracellular domain of human TGF beta RII and IgG1 Fc, on CsA nephrotoxicity in mice. Subcutaneous injection of CsA (25 mg/kg/d) was given daily to mice maintained on a low-sodium diet. On days 1 and 7, an expression vector carrying cDNA for either TGF beta RII/IgG Fc or beta-galactosidase was transfected into the skeletal muscles by electroporation. At 2 or 3 weeks of CsA administration, plasma and renal TGF beta 1 levels, and tubulointerstitial injury and fibrosis were evaluated. After 2 weeks of CsA administration, plasma and renal TGF beta 1 levels increased to the maximum and then declined toward the baseline levels. Renal TGF beta 1 mRNA remained elevated until 3 weeks. Tubulointerstitial alterations became appreciable in 2 weeks and intensified by 3 weeks. At 2 weeks, the TGF beta RII/IgG Fc intervention abolished the increase in plasma TGF beta 1, attenuated the increase in renal TGF beta 1 by 50%, and markedly suppressed the histologic alterations. At 3 weeks, the histologic alterations remained markedly suppressed by the intervention, with no appreciable effects on the renal TGF beta 1 mRNA and protein. The introduction of TGF beta RII/IgG Fc by gene transfer effectively abrogated CsA-induced tubulointerstitial alterations. Suppression of tubulointerstitial changes was evident at 3 weeks when renal TGF beta 1 mRNA and protein were comparable to those with CsA alone, indicating that early anti-TGF beta intervention is effective in suppressing the progression of CsA nephrotoxicity despite persistent increases in renal TGF beta 1 expression.
    Transplantation 06/2004; 77(9):1433-42. DOI:10.1097/01.TP.0000121502.60664.AB · 3.78 Impact Factor
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    ABSTRACT: We examined the in vivo function of the angiotensin II type 1 receptor (Agtr1) on macrophages in renal fibrosis. Fourteen days after the induction of unilateral ureteral obstruction (UUO), wild-type mice reconstituted with marrow lacking the Agtr1 gene (Agtr1(-/-)) developed more severe interstitial fibrosis with fewer interstitial macrophages than those in mice reconstituted with Agtr1(+/+) marrow. These differences were not observed at day 5 of UUO. The expression of profibrotic genes - including TGF-beta1, alpha1(I) collagen, and alpha1(III) collagen - was substantially higher in the obstructed kidneys of mice with Agtr1(-/-) marrow than in those with Agtr1(+/+) marrow at day 14 but not at day 5 of UUO. Mice with Agtr1(-/-) marrow were characterized by reduced numbers of peripheral-blood monocytes and macrophage progenitors in bone marrow. In vivo assays revealed a significantly impaired phagocytic capability in Agtr1(-/-) macrophages. In vivo treatment of Agtr1(+/+) mice with losartan reduced phagocytic capability of Agtr1(+/+) macrophages to a level comparable to that of Agtr1(-/-) macrophages. Thus, during urinary tract obstruction, the Agtr1 on bone marrow-derived macrophages functions to preserve the renal parenchymal architecture, and this function depends in part on its modulatory effect on phagocytosis.
    Journal of Clinical Investigation 01/2003; 110(12):1859-68. DOI:10.1172/JCI15045 · 13.77 Impact Factor
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    ABSTRACT: Accumulating data show that excess of angiotensin II (Ang II) is involved in cardiac fibrosis. Many experimental studies suggested that Ang II induces cardiac fibrosis not by its blood pressure-raising action, but rather by a direct action on the heart. However, it has been difficult to distinguish the local and systemic actions in vivo. Recent genetic technology sheds new light on this problem. This review focuses on the recent advances and newly arising issues regarding the mechanism of Ang II-induced cardiac fibrosis.
    Trends in Cardiovascular Medicine 10/1999; 9(7):180-184. DOI:10.1016/S1050-1738(00)00018-9 · 2.07 Impact Factor
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    ABSTRACT: The role of the endothelium, is now known to encompass the generation of many potent cytokines which impact endothelial cells, adjacent tissue such as smooth muscle cells, and distant sites in an autocrine, paracrine, and endocrine manner, respectively. This review addresses two of these cytokines, nitric oxide and endothelin, and describes how each effects the functions of endothelial cells, including regulation of platelet aggregation and coagulation, regulation of vasomotor tone, modulation of inflammation, and the regulation of cellular proliferation. The emphasis is on the increasingly recognized importance of the autocrine and paracrine mechanisms by which nitric oxide and endothelin act. In particular, autoinduction of endothelin is proposed as a central mechanism underlying endothelin''s renowned effects. Additionally, specific nitric oxide/endothelin interactions are discussed by which each cytokine modulates the production and actions of the other. The net effect observed in a variety of physiological and pathophysiological settings, therefore, reflects a balance of these opposing functions.
    Pediatric Nephrology 03/1995; 9(2):235-244. DOI:10.1007/BF00860758 · 2.88 Impact Factor
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    ABSTRACT: Hepatocyte growth factor (HGF), a novel heparin-binding peptide growth factor of MW 97-kDa, is a potent mitogen for parenchymal hepatocytes. HGF is present in normal serum and increases following liver injury or partial hepatectomy. In addition to liver, HGF mRNA has been detected in kidney. In cultured rabbit proximal tubule cells, recombinant human HGF (10−10 M) increased DNA synthesis, measured as [3H] thymidine incorporation, from 1345±213 to 2931±636 cpm/106 cells; n=9; p<0.005). HGF was found to exert mitogenic effects at lower concentrations than epidermal growth factor (EGF), with half maximal effects seen at 6 × 10−11 M compared to 7 ×10−10 M for EGF. HGF was additive with EGF in stimulating [3H] thymidine incorporation. In addition to rabbit proximal tubule cells, HGF increased proliferation in a cultured mouse proximal tubule cell line, MCT, and in rat glomerular epithelial cells. In contrast, HGF did not stimulate proliferation of either rat mesangial cells or a rat aortic smooth muscle cell line, A7r5. The HGF receptor is the product of the c-met proto-oncogene. C-met mRNA was detected in total kidney and in cultured proximal tubule cells but was not detected in cultured mesangial cells. In contrast, HGF mRNA was detected in mesangial cells but not in cultured proximal tubule cells. Preincubation of rabbit proximal tubule cells with the tyrosine kinase inhibitor, genistein (50 μM), prevented HGF-stimulation of [3H] thymidine incorporation. In LiCl pretreated rabbit proximal tubule cells loaded with [3H] myoinositol, HGF increased total inositol phosphate release, measured by anion exchange chromatography (control: 2181±414 vs HGF: 2609±478 cpm/16 cells; n=6; p<0.05). Although genistein did not affect baseline phosphoinositide hydrolysis, it inhibited the HGF stimulation. Thus, HGF is mitogenic for cultured proximal tubule cells as well as glomerular epithelial cells. Inhibition of proliferation and PI turnover by genistein suggests that HGF's actions are mediated in part by tyrosine kinase activity. In mammalian kidney, HGF relesased from mesangial cells may serve as a paracrine activator of the adjacent epithelial cells.
    Life Sciences 01/1993; 52(13-52):1091-1100. DOI:10.1016/0024-3205(93)90430-B · 2.30 Impact Factor

Publication Stats

153 Citations
24.80 Total Impact Points

Institutions

  • 1993–2004
    • Vanderbilt University
      • • Department of Pediatrics
      • • Department of Neurology
      Нашвилл, Michigan, United States