Transforming growth factor-beta 1 expression and phenotypic modulation in the kidney of hypertensive rats.
We have previously reported that renal mRNA levels for transforming growth factor-beta 1, fibronectin, and collagens were increased in 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) with severe nephrosclerosis. To elucidate the mechanism of hypertension-induced nephrosclerosis, we examined gene expression and localization of transforming growth factor-beta 1 and cellular phenotype in the kidney of 25-week-old SHRSP with moderate renal damage. Renal mRNA was measured by Northern blot analysis. The localization of transforming growth factor-beta 1 and cellular phenotype was determined by immunohistochemistry. In the kidney of 25-week-old SHRSP, renal transforming growth factor-beta 1 mRNA was elevated compared with Wistar-Kyoto rats (WKY), whereas renal collagen mRNAs of SHRSP were not increased. Immunoreactive transforming growth factor-beta 1 in SHRSP was mainly localized in glomerular cells. Furthermore, alpha-smooth muscle actin and desmin were significantly expressed in SHRSP glomerular cells, in contrast to negligible expression of these proteins in WKY. alpha-Smooth muscle actin staining was also observed in interstitial cells, and vimentin, another phenotypic marker, was expressed in atrophic tubular cells of SHRSP, despite no staining of these proteins in WKY. Furthermore, all these phenotypic changes in SHRSP were associated with increased cell proliferation, as shown by the increased number of proliferating cell nuclear antigen-positive cells. Treatment of SHRSP with cilazapril and nifedipine (from the age of 13 to 25 weeks) prevented the increase in transforming growth factor-beta 1 expression and the cellular phenotypic modulation and was accompanied by a reduction of urinary albumin excretion and inhibition of cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
Hamaguchi
A
A
Department of Pharmacology, Osaka City University Medical School, Japan.
Kim
S
S
Ohta
K
K
Yagi
K
K
Yukimura
T
T
Miura
K
K
Fukuda
T
T
Iwao
H
H
D000199:Actins / Q000032:analysis; D000818:Animals; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D017315:Cilazapril / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression; D005819:Genetic Markers; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D007150:Immunohistochemistry; D007668:Kidney / Q000737:chemistry / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000737:chemistry / Q000378:metabolism; D008297:Male; D009400:Nephrosclerosis / Q000209:etiology / Q000235:genetics; D009543:Nifedipine / Q000494:pharmacology / Q000627:therapeutic use; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013194:Staining and Labeling; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics*; D014746:Vimentin / Q000032:analysis
D000199:Actins; D005819:Genetic Markers; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014746:Vimentin; D017315:Cilazapril; D009543:Nifedipine