Differential growth factor-induced modulation of proteoglycans synthesized by normal human renal versus cyst-derived...

In polycystic kidney disease (PKD), there is an insiduous enlargement of the kidneys and dilation of the renal tubules associated with extracellular matrix (ECM) alterations. The latter include thickening of tubular basement membrane and decreased synthesis of sulfated proteoglycan (PG). Because PKD is believed to be a disorder of cell growth and deranged ECM metabolism, it is conceivable that the formation of cystic tubules may be modulated by certain growth factors (GF) that influence the synthesis of ECM glycoproteins. In this study, the effect of various GF, i.e., epidermal, hepatocyte (HGF) and transforming (TGF), and triiodothyronine on the PG synthesized by normal human kidney (NK) epithelial cells and cells derived from cysts of patients with autosomal dominant PKD (ADPKD) was assessed. (35S) sulfate incorporation studies revealed that, among various GF, HGF and TGF-beta 1 had the maximal stimulatory effect on the synthesis of PG extracted from ADPKD cells. A minimal increase in the PG synthesis was observed in NK cells; however, PG synthesized under the influence of HGF or TGF-beta 1 were of relatively higher molecular weight, with a shift of K(av) from 0.28 to 0.12, as ascertained by Sepharose-6B chromatography. PG synthesized by ADPKD cells had a K(av) = 0.18, and it did not change with the GF treatment. The charge-density characteristics of PG of ADPKD cells were relatively lower than those of NK cells, and they were unaffected by HGF or TGF-beta 1 treatment. Interestingly, both the HGF and TGF-beta 1 significantly affected posttranslational modifications of PG.(ABSTRACT TRUNCATED AT 250 WORDS)