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(Hypertension. 1995;26:199-207.)
© 1995 American Heart Association, Inc.

Articles

Transforming Growth Factor-ß1 Expression and Phenotypic Modulation in the Kidney of Hypertensive Rats

Akinori Hamaguchi; Shokei Kim; Kensuke Ohta; Keiko Yagi; Tokihito Yukimura; Katsuyuki Miura; Taneo Fukuda; Hiroshi Iwao

From the Department of Pharmacology, Osaka City University Medical School, and the Department of Drug Safety Research (T.F.), Eisai Co, Ltd, Gifu, Japan.

Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1-4-54 Asahimachi, Abeno, Osaka 545, Japan.

Abstract We have previously reported that renal mRNA levels for transforming growth factor-ß1, 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-ß1 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-ß1 and cellular phenotype was determined by immunohistochemistry. In the kidney of 25-week-old SHRSP, renal transforming growth factor-ß1 mRNA was elevated compared with Wistar-Kyoto rats (WKY), whereas renal collagen mRNAs of SHRSP were not increased. Immunoreactive transforming growth factor-ß1 in SHRSP was mainly localized in glomerular cells. Furthermore, -smooth muscle actin and desmin were significantly expressed in SHRSP glomerular cells, in contrast to negligible expression of these proteins in WKY. -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-ß1 expression and the cellular phenotypic modulation and was accompanied by a reduction of urinary albumin excretion and inhibition of cell proliferation. These results indicated that sustained hypertension causes the increased glomerular transforming growth factor-ß1 expression and cellular phenotypic modulation, which may play an important role in the progression of glomerulosclerosis and tubulointerstitial fibrosis in hypertension.

Key Words: transforming growth factor-ß • phenotype • hypertension, genetic • nephrosclerosis • antihypertensive agents

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