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1.
Kidney Int ; 58(6): 2367-76, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11115070

ABSTRACT

BACKGROUND: The biologic responses to transforming growth factor-beta (TGF-beta) suggest many potential therapeutic applications; however, in the only clinical trial to examine the effect of the systemic administration of a TGF-beta isoform, patients experienced significant but reversible declines in renal function. We studied the effects of administering human recombinant TGF-beta2 to adult mice. METHODS: The effect of daily administration of TGF-beta2 on tissue vasoconstriction, tissue levels of endothelin and angiotensin II, tissue hypoxia, and renal fibrosis were examined. RESULTS: Daily administration of TGF-beta2 at 10 or 100 microg/kg caused apparent tissue vasoconstriction that was visualized by vascular casting, with the largest impact seen in the kidney. Tissue levels of endothelin 1 and angiotensin II were significantly elevated in kidneys of treated mice, as was urinary thromboxane beta2. Renal fibrosis was observed in the cortical tubular interstitium and vasculature, particularly at the cortical-medullary junction and medullary vasa recta; however, glomerular sclerosis was not observed. Fibrosis was correlated to focal tissue hypoxia as determined by immunohistochemical detection of tissue bound pimondazole. CONCLUSION: We conclude that there are significant histopathologic consequences, focused in the kidney, resulting from the daily administration of high doses of human recombinant TGF-beta2, and we propose that selective vascular constriction with consequent tissue hypoxia is a contributing factor.


Subject(s)
Kidney Diseases/chemically induced , Kidney Diseases/pathology , Kidney/pathology , Transforming Growth Factor beta/toxicity , Vasoconstriction/drug effects , Angiotensin II/analysis , Animals , Corrosion Casting , Endothelin-1/analysis , Fibrosis , Glomerular Filtration Rate , Humans , Hypoxia/pathology , Ischemia/pathology , Kidney/blood supply , Kidney/chemistry , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Procollagen/analysis , Recombinant Proteins/toxicity , Transforming Growth Factor beta2
2.
J Am Soc Nephrol ; 10(6): 1264-73, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10361864

ABSTRACT

The expression of transforming growth factor-beta (TGF-beta) correlates with the incidence of renal glomerular and interstitial injury, however, nothing is known of the effect of these proteins on renal hemodynamics. This study examines the renal hemodynamic and morphologic effects of recombinant human TGF-beta2 in normal male Sprague Dawley rats. Acute infusion of TGF-beta (1.2 microg/kg per min) induced no hemodynamic changes, except for a modest though significant fall in mean arterial pressure. Administering TGF-beta2 at varying doses (20, 100, and 400 microg/kg) for 9 wk caused modest increases in systolic BP and proteinuria and minimal tubular interstitial fibrosis, however, renal hemodynamic end points were not significantly altered. TGF-beta2 (800 microg/kg) was also administered to volume-depleted rats for 7 consecutive days. In contrast to the findings in volume-replete animals, administration of TGF-beta2 to volume-depleted rats caused a marked reduction in GFR and medullary blood flow. Histologic fibrosis of the medullary vasa recta and cortical interstitium was seen, but glomeruli were unaffected. Thus, acute and short-term chronic TGF-beta2 administration did not induce major renal changes in the volume-replete state, however, TGF-beta2 combined with volume depletion caused medullary hypoperfusion and reduced GFR.


Subject(s)
Kidney/drug effects , Kidney/pathology , Renal Circulation/drug effects , Transforming Growth Factor beta/administration & dosage , Analysis of Variance , Animals , Diuretics/pharmacology , Dose-Response Relationship, Drug , Drug Administration Schedule , Furosemide/pharmacology , Hemodynamics/drug effects , Infusions, Intravenous , Kidney Function Tests , Laser-Doppler Flowmetry , Male , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Recombinant Proteins/administration & dosage , Reference Values
3.
Endocrinology ; 130(3): 1318-24, 1992 Mar.
Article in English | MEDLINE | ID: mdl-1311236

ABSTRACT

To better understand the in vivo bone-inductive properties of recombinant human (rh) BMP-2, we examined the ability of the protein to alter the phenotype of a bone marrow stromal cell line. W-20-17. rhBMP-2 increased alkaline phosphatase activity in W-20-17 cells in a dose-responsive manner in the absence of an effect on proliferation. The induction of alkaline phosphatase activity was not apparent until 12 h after rhBMP-2 treatment had begun and was effectively eliminated by cotreatment with cycloheximide, suggesting a requirement for protein synthesis. Continued treatment of W-20-17 cells with rhBMP-2 for 8 days resulted in a significant increase, compared to control cultures, in the production of cellular cAMP in response to a PTH challenge. In addition, 4-day treatment with rhBMP-2 induced osteocalcin levels in W-20-17 cells. These results indicate that rhBMP-2 induces the expression of several markers associated with the osteoblast phenotype in W-20-17 cells and raises the possibility that BMP-2 may be involved in the differentiation of osteoblasts from progenitor cells resident in bone marrow.


Subject(s)
Osteoblasts/cytology , Proteins/pharmacology , Alkaline Phosphatase/metabolism , Animals , Blotting, Northern , Bone Morphogenetic Proteins , Cell Differentiation/drug effects , Cells, Cultured , Cyclic AMP/metabolism , Cycloheximide/pharmacology , DNA/metabolism , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Humans , Mice , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteocalcin/metabolism , Parathyroid Hormone/pharmacology , Phenotype , Recombinant Proteins/pharmacology , Thymidine/metabolism , Tritium
4.
Connect Tissue Res ; 20(1-4): 313-9, 1989.
Article in English | MEDLINE | ID: mdl-2612162

ABSTRACT

Using a novel purification scheme, we have characterized BMP as a 30kD fraction. After reduction, which destroys biological activity, this fraction was shown to be comprised of individual polypeptides with molecular weights of 30kD, 18kD and 16kD. Molecular cloning of these polypeptides resulted in the identification of 4 previously undescribed genes (BMP-1, BMP-2A, BMP-2B, and BMP-3) each of which is capable of directing de novo cartilage formation in vivo. While BMP-1 appears to be unrelated to other known growth factors, the derived amino acid sequence of BMP-2A, 2B, and 3 indicate that they are new members of the TGFb gene family. BMP-1, 2A and 2B are expressed in rat embryos during morphogenesis and can be localized by in situ hybridization to developing limb buds. BMP-3 localizes to neural ectoderm and later on in development to newly forming periosteum. Comparisons to other members of the TGFb family suggest that these newly identified BMPs are involved in pattern formation during early skeletal development.


Subject(s)
Bone and Bones/analysis , Membrane Proteins/isolation & purification , RNA, Messenger/analysis , Amino Acid Sequence , Animals , Bone Development/physiology , Bone and Bones/metabolism , Bone and Bones/physiology , Cloning, Molecular , Membrane Proteins/genetics , Membrane Proteins/metabolism , Peptides/genetics , Peptides/isolation & purification , Peptides/metabolism , RNA, Messenger/metabolism , Rats
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