Back to Search
Start Over
Matrix metalloproteinase 2 induces epithelial-mesenchymal transition in proximal tubules from the luminal side and progresses fibrosis in mineralocorticoid/salt-induced hypertensive rats
- Source :
- Journal of hypertension. 29(12)
- Publication Year :
- 2011
-
Abstract
- Objectives Excess mineralocorticoids such as deoxycorticosterone acetate (DOCA) together with salt are known to cause tubulointerstitial fibrosis, but the mechanisms underlying fibrosis progression are unclear. Therefore, we investigated the role of matrix metalloproteinase 2 (MMP2) in the epithelial-mesenchymal transition and fibrosis progression. Methods Uninephrectomized rats drank 0.9% NaCl and 0.3% KCl solution and were treated with DOCA alone, DOCA + spironolactone, or vehicle for 1, 4, or 8 weeks. SBP, kidney function and morphology, and kidney and urine MMP2 activity were compared among the groups. Results At week 4, the DOCA-treated group exhibited hypertension, tubulointerstitial fibrosis, increased MMP2 activity in the kidney and urine, and overexpression of MMP2 in proximal tubule cells and MMP14 in apical membranes; these results were more pronounced at week 8. At week 8, the proximal tubule cell apicolateral surface proteins villin, claudin 2, and E-cadherin were downregulated, and the mesenchymal marker α-smooth muscle actin was upregulated in the tubulointerstitium of DOCA-treated rats. These DOCA/salt-induced changes (except for hypertension) and fibrosis progression observed at week 8 were reversed by TISAM (a selective MMP2 inhibitor), which was administered from week 4 to week 8. All of the effects of DOCA/salt at week 8 were attenuated by spironolactone. Conclusion Eight weeks of treatment with DOCA/salt activated MMP2, primarily on the apical surface of proximal tubule cells, which induced epithelial-mesenchymal transition from the luminal side and promoted tubulointerstitial fibrosis progression. These MMP2-induced changes occurred via downstream processes regulated by mineralocorticoid receptors.
- Subjects :
- Male
medicine.medical_specialty
Epithelial-Mesenchymal Transition
Physiology
medicine.drug_class
Sodium Chloride
Spironolactone
Kidney
Nephrectomy
Kidney Tubules, Proximal
Rats, Sprague-Dawley
chemistry.chemical_compound
Fibrosis
Internal medicine
Internal Medicine
medicine
Animals
Epithelial–mesenchymal transition
Desoxycorticosterone
biology
urogenital system
business.industry
Kidney metabolism
medicine.disease
Rats
Disease Models, Animal
medicine.anatomical_structure
Endocrinology
chemistry
Mineralocorticoid
Hypertension
biology.protein
Tubulointerstitial fibrosis
Disease Progression
Matrix Metalloproteinase 2
Nephritis, Interstitial
Drug Therapy, Combination
Collagen
Cardiology and Cardiovascular Medicine
Villin
business
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 14735598
- Volume :
- 29
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Journal of hypertension
- Accession number :
- edsair.doi.dedup.....77cdaf435750fe8c2b8895a08c45be08