title: Spironolactone suppresses peritubular capillary loss and prevents deoxycorticosterone acetate/salt-induced tubulointerstitial fibrosis.
abstract: We examined whether and how peritubular capillary (PTC) loss in the renal cortex contributes to the development of deoxycorticosterone acetate (DOCA)/salt-induced tubulointerstitial fibrosis. Uninephrectomized rats provided with 0.9% NaCl/0.3% KCl drinking solution ad libitum were divided into control, DOCA, and spironolactone groups, which were administered vehicle, DOCA alone, and DOCA plus spironolactone for 1 (initial phase) and 4 weeks (delayed phase), respectively. Exposure to DOCA initiated a sequence of events that initially involved reduced PTC density, followed by a delayed response that involved further reduced PTC density, development of tubulointerstitial fibrosis and hypertension, enhanced expression of transforming growth factor-beta1 and connective tissue growth factor, and impaired renal function. Concomitant with the reduced PTC density, the 2 hypoxia-responsive angiogenic factors (vascular endothelial growth factor and hypoxia-inducible factor-1alpha) and the antiangiogenic factor (thrombospondin-1) were upregulated in cortical tubular cells of the DOCA group during the 2 phases and only in the delayed phase, respectively. In the DOCA group, PTC endothelial cell apoptosis was enhanced during the 2 phases, and PTC endothelial cell proliferation was inhibited in the delayed phase. In accordance with upregulation of thrombospondin-1, p53 expression was enhanced in the DOCA group in the delayed phase. The initial and delayed effects of DOCA were blocked in the spironolactone group. We conclude that exposure to DOCA initially caused the reduced PTC density associated with enhanced apoptosis independent of thrombospondin-1, which induced tubulointerstitial fibrosis via p53-mediated thrombospondin-1 activation, and spironolactone conversely corrected the effects of DOCA to prevent fibrosis.
authors.affiliation: Department of Nephrology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iwazu
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Muto
authors.forename: Genro
authors.initials: G
authors.lastname: Fujisawa
authors.forename: Eiko
authors.initials: E
authors.lastname: Nakazawa
authors.forename: Koji
authors.initials: K
authors.lastname: Okada
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
authors.forename: Eiji
authors.initials: E
authors.lastname: Kusano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002196:Capillaries / Q000378:metabolism / Q000473:pathology*; D055513:Connective Tissue Growth Factor; D003900:Desoxycorticosterone; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007684:Kidney Tubules / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D013148:Spironolactone / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C526316:CCN2 protein, rat; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000451:Mineralocorticoid Receptor Antagonists; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D055513:Connective Tissue Growth Factor; D013148:Spironolactone; D003900:Desoxycorticosterone; D012965:Sodium Chloride