Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction

A. Miyajima, J. Chen, C. Lawrence, S. Ledbetter, R. A. Soslow, Joshua M. Stern, S. Jha, J. Pigato, M. L. Lemer, D. P. Poppas, Jr Vaughan E.D., D. Felsen

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Abstract

Background. Unilateral ureteral obstruction (UUO) is characterized by progressive renal atrophy, renal interstitial fibrosis, an increase in renal transforming growth factor-β (TGF-β), and renal tubular apoptosis. The present study was undertaken to determine the effect of a monoclonal antibody to TGF-β (1D11) in UUO. Methods. Mechanical stretch was applied to tubular epithelial cells (NRK-52E) by a computer-assisted system. Three doses of 1D11 (either 0.5, 2, or 4 mg/rat) were administered to rats one day prior to UUO and every two days thereafter, and kidneys were harvested at day 13. Fibrosis was assessed by measuring tissue hydroxyproline and mRNA for collagen and fibronectin. Apoptosis was assessed with the terminal deoxy transferase uridine triphosphate nick end-labeling assay. TGF-β levels were determined by bioassay. Western blot and immunostaining were used to identify proliferating cell nuclear antigen (PCNA), p53, bcl-2, and inducible nitric oxide synthase (iNOS). Results. Stretch significantly induced apoptosis in NRK-52E cells, which was accompanied by an increased release of TGF-β; 1D11 (10 μg/mL) totally inhibited stretch-induced apoptosis. Control obstructed kidney contained 20-fold higher TGF-β as compared with its unobstructed kidney; 1D11 neutralized tissue TGF-β of the obstructed kidney. Control obstructed kidney exhibited significantly more fibrosis and tubular apoptosis than its unobstructed counterpart, which was blunted by 1D11. In contrast, 1D11 significantly increased tubular proliferation. p53 immunostaining was localized to renal tubular nuclei of control obstructed kidney and was diminished by 1D11. In contrast, bcl-2 was up-regulated in the 1D11-treated obstructed kidney. Total NOS activity and iNOS activity of the obstructed kidney were increased by 1D11 treatment. Conclusion. The present study strongly suggests that an antibody to TGF-β is a promising agent to prevent renal tubular fibrosis and apoptosis in UUO.

Original languageEnglish (US)
Pages (from-to)2301-2313
Number of pages13
JournalKidney International
Volume58
Issue number6
DOIs
StatePublished - 2000
Externally publishedYes

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Ureteral Obstruction
Transforming Growth Factors
Apoptosis
Kidney
Antibodies
Fibrosis
Nitric Oxide Synthase Type II
Uridine Triphosphate
Hydroxyproline
Computer Systems
Proliferating Cell Nuclear Antigen
Transferases
Fibronectins
Biological Assay
Atrophy

Keywords

  • Cell death
  • Fibrosis
  • Monoclonal antibody
  • Progressive renal atrophy
  • Renal tubular obstruction

ASJC Scopus subject areas

  • Nephrology

Cite this

Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction. / Miyajima, A.; Chen, J.; Lawrence, C.; Ledbetter, S.; Soslow, R. A.; Stern, Joshua M.; Jha, S.; Pigato, J.; Lemer, M. L.; Poppas, D. P.; Vaughan E.D., Jr; Felsen, D.

In: Kidney International, Vol. 58, No. 6, 2000, p. 2301-2313.

Research output: Contribution to journalArticle

Miyajima, A, Chen, J, Lawrence, C, Ledbetter, S, Soslow, RA, Stern, JM, Jha, S, Pigato, J, Lemer, ML, Poppas, DP, Vaughan E.D., J & Felsen, D 2000, 'Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction', Kidney International, vol. 58, no. 6, pp. 2301-2313. https://doi.org/10.1046/j.1523-1755.2000.00414.x
Miyajima, A. ; Chen, J. ; Lawrence, C. ; Ledbetter, S. ; Soslow, R. A. ; Stern, Joshua M. ; Jha, S. ; Pigato, J. ; Lemer, M. L. ; Poppas, D. P. ; Vaughan E.D., Jr ; Felsen, D. / Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction. In: Kidney International. 2000 ; Vol. 58, No. 6. pp. 2301-2313.
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abstract = "Background. Unilateral ureteral obstruction (UUO) is characterized by progressive renal atrophy, renal interstitial fibrosis, an increase in renal transforming growth factor-β (TGF-β), and renal tubular apoptosis. The present study was undertaken to determine the effect of a monoclonal antibody to TGF-β (1D11) in UUO. Methods. Mechanical stretch was applied to tubular epithelial cells (NRK-52E) by a computer-assisted system. Three doses of 1D11 (either 0.5, 2, or 4 mg/rat) were administered to rats one day prior to UUO and every two days thereafter, and kidneys were harvested at day 13. Fibrosis was assessed by measuring tissue hydroxyproline and mRNA for collagen and fibronectin. Apoptosis was assessed with the terminal deoxy transferase uridine triphosphate nick end-labeling assay. TGF-β levels were determined by bioassay. Western blot and immunostaining were used to identify proliferating cell nuclear antigen (PCNA), p53, bcl-2, and inducible nitric oxide synthase (iNOS). Results. Stretch significantly induced apoptosis in NRK-52E cells, which was accompanied by an increased release of TGF-β; 1D11 (10 μg/mL) totally inhibited stretch-induced apoptosis. Control obstructed kidney contained 20-fold higher TGF-β as compared with its unobstructed kidney; 1D11 neutralized tissue TGF-β of the obstructed kidney. Control obstructed kidney exhibited significantly more fibrosis and tubular apoptosis than its unobstructed counterpart, which was blunted by 1D11. In contrast, 1D11 significantly increased tubular proliferation. p53 immunostaining was localized to renal tubular nuclei of control obstructed kidney and was diminished by 1D11. In contrast, bcl-2 was up-regulated in the 1D11-treated obstructed kidney. Total NOS activity and iNOS activity of the obstructed kidney were increased by 1D11 treatment. Conclusion. The present study strongly suggests that an antibody to TGF-β is a promising agent to prevent renal tubular fibrosis and apoptosis in UUO.",
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AU - Miyajima, A.

AU - Chen, J.

AU - Lawrence, C.

AU - Ledbetter, S.

AU - Soslow, R. A.

AU - Stern, Joshua M.

AU - Jha, S.

AU - Pigato, J.

AU - Lemer, M. L.

AU - Poppas, D. P.

AU - Vaughan E.D., Jr

AU - Felsen, D.

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N2 - Background. Unilateral ureteral obstruction (UUO) is characterized by progressive renal atrophy, renal interstitial fibrosis, an increase in renal transforming growth factor-β (TGF-β), and renal tubular apoptosis. The present study was undertaken to determine the effect of a monoclonal antibody to TGF-β (1D11) in UUO. Methods. Mechanical stretch was applied to tubular epithelial cells (NRK-52E) by a computer-assisted system. Three doses of 1D11 (either 0.5, 2, or 4 mg/rat) were administered to rats one day prior to UUO and every two days thereafter, and kidneys were harvested at day 13. Fibrosis was assessed by measuring tissue hydroxyproline and mRNA for collagen and fibronectin. Apoptosis was assessed with the terminal deoxy transferase uridine triphosphate nick end-labeling assay. TGF-β levels were determined by bioassay. Western blot and immunostaining were used to identify proliferating cell nuclear antigen (PCNA), p53, bcl-2, and inducible nitric oxide synthase (iNOS). Results. Stretch significantly induced apoptosis in NRK-52E cells, which was accompanied by an increased release of TGF-β; 1D11 (10 μg/mL) totally inhibited stretch-induced apoptosis. Control obstructed kidney contained 20-fold higher TGF-β as compared with its unobstructed kidney; 1D11 neutralized tissue TGF-β of the obstructed kidney. Control obstructed kidney exhibited significantly more fibrosis and tubular apoptosis than its unobstructed counterpart, which was blunted by 1D11. In contrast, 1D11 significantly increased tubular proliferation. p53 immunostaining was localized to renal tubular nuclei of control obstructed kidney and was diminished by 1D11. In contrast, bcl-2 was up-regulated in the 1D11-treated obstructed kidney. Total NOS activity and iNOS activity of the obstructed kidney were increased by 1D11 treatment. Conclusion. The present study strongly suggests that an antibody to TGF-β is a promising agent to prevent renal tubular fibrosis and apoptosis in UUO.

AB - Background. Unilateral ureteral obstruction (UUO) is characterized by progressive renal atrophy, renal interstitial fibrosis, an increase in renal transforming growth factor-β (TGF-β), and renal tubular apoptosis. The present study was undertaken to determine the effect of a monoclonal antibody to TGF-β (1D11) in UUO. Methods. Mechanical stretch was applied to tubular epithelial cells (NRK-52E) by a computer-assisted system. Three doses of 1D11 (either 0.5, 2, or 4 mg/rat) were administered to rats one day prior to UUO and every two days thereafter, and kidneys were harvested at day 13. Fibrosis was assessed by measuring tissue hydroxyproline and mRNA for collagen and fibronectin. Apoptosis was assessed with the terminal deoxy transferase uridine triphosphate nick end-labeling assay. TGF-β levels were determined by bioassay. Western blot and immunostaining were used to identify proliferating cell nuclear antigen (PCNA), p53, bcl-2, and inducible nitric oxide synthase (iNOS). Results. Stretch significantly induced apoptosis in NRK-52E cells, which was accompanied by an increased release of TGF-β; 1D11 (10 μg/mL) totally inhibited stretch-induced apoptosis. Control obstructed kidney contained 20-fold higher TGF-β as compared with its unobstructed kidney; 1D11 neutralized tissue TGF-β of the obstructed kidney. Control obstructed kidney exhibited significantly more fibrosis and tubular apoptosis than its unobstructed counterpart, which was blunted by 1D11. In contrast, 1D11 significantly increased tubular proliferation. p53 immunostaining was localized to renal tubular nuclei of control obstructed kidney and was diminished by 1D11. In contrast, bcl-2 was up-regulated in the 1D11-treated obstructed kidney. Total NOS activity and iNOS activity of the obstructed kidney were increased by 1D11 treatment. Conclusion. The present study strongly suggests that an antibody to TGF-β is a promising agent to prevent renal tubular fibrosis and apoptosis in UUO.

KW - Cell death

KW - Fibrosis

KW - Monoclonal antibody

KW - Progressive renal atrophy

KW - Renal tubular obstruction

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