PLATELET-DERIVED GROWTH FACTOR-BB INDUCES RENAL TUBULOINTERSTITIAL MYOFIBROBLAST FORMATION AND TUBULOINTERSTITIAL FIBROSIS

Tubulointerstitial fibrosis correlates closely with renal function, al though the mechanism regulating tubulointerstitial fibrogenesis remain s poorly understood Since platelet-derived growth factor (PDGF) is a g rowth factor for fibroblasts, we examined the effect of daily (for 7 d ays) PDGF-AA or PDGF-BB administration on renal tubulointerstitial arc hitecture in rats. PDGF-AA administration at a dose of 5 mg/kg did not affect the renal tubulointerstitum. By comparison, PDGF-BB induced do se-dependent renal tubulointerstitial cell proliferation and fibrosis. At 5 mg/kg, PDGF-BB increased BrdU labeling in tubulointerstitial fib roblasts at 24 hours (19-fold), which peaked at 72 hours (23-fold) wit h bromodeoxyuridine uptake returning to control values by 7 days. Tubu lointerstitial proliferation was associated with the differentiation o f these cells into myofibroblasts as evidenced by alpha-smooth muscle actin expression beginning on day 3 The expression of alpha-smooth mus cle actin peaked on day 5 and had markedly declined by day 21. In addi tion, apoptotic cells were identified within the tubulointerstitum on day 3 and Progressively increased through day 7, suggesting that the d isappearance of myofibroblasts may have occurred through apoptosis. Th ese changes were accompanied by increased expression of alpha 1 (III) collagen mRNA and interstitial accumulation of type III collagen withi n the renal cortex. By morphometric analysis, an approximately twofold increase in collagen III immunolabeling within the interstitial compa rtment was evident at 24 hours and peaked on days 5 to 7 (approximatel y fourfold). These data suggest that PDGF-BB may be an important media tor of tubulointerstitial hyperplasia and fibrosis.