title: Matrix metalloproteinase 2 induces epithelial-mesenchymal transition in proximal tubules from the luminal side and progresses fibrosis in mineralocorticoid/salt-induced hypertensive rats.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Nephrology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors: Yoshitaka
authors: Y
authors: Iwazu
authors: Shigeaki
authors: S
authors: Muto
authors: Ichiro
authors: I
authors: Hirahara
authors: Genro
authors: G
authors: Fujisawa
authors: Shin-ichi
authors: S
authors: Takeda
authors: Eiji
authors: E
authors: Kusano
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D003900:Desoxycorticosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004359:Drug Therapy, Combination; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005355:Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000494:pharmacology*; D013148:Spironolactone / Q000494:pharmacology
chemical_list: D013148:Spironolactone; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D003094:Collagen; D020778:Matrix Metalloproteinase 2