Journal of the American Society of Nephrology 47 Differential Growth Factor-Induced Modulation of Proteoglycans Synthesized by Normal Human Renal Versus Cyst-Derived Cells” Judith Kovacs, Frank A. Carone,2 Zheng Z. Liu, Sakie Nakumara, Anil Kumar, and Yashpal S. Kanwar J. Kovacs. F.A. Carone, Z.Z. Liu, S. Nakumara, A. Kumar, Y,S, Kanwar, Department of Pathology, Northwestern University Medical School, Chicago, IL (J. Am. Soc. Nephrol. 1994; 5:47-54) ABSTRACT In polycystic kidney disease (PKD), there is an insi- duous 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 syn- thesis of sulfated proteoglycan (PG). Because PKD is believed to be a disorder of cell growth and de- ranged ECM metabolism, it is conceivable that the formation of cystic tubules may be modulated by certain growth factors (GF) that influence the synthe- sis 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- 31 had the maximal stimu- Iatory 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-flI were of rela- tively higher molecular weight, with a shift of K0 from 0.28 to 0.12, as ascertained by Sepharose-6B chro- matography. PG synthesized by ADPKD cells had a Kay 0.18, and it did not change with the GF treat- ment. 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-jfl treatment. Interestingly, both the HGF and TGF- 31 I Received January 10, 1994. Accepted March 9, 1994. 2 Correspondence to Dr. F.A. Carone Department of Pathology, Northwestern University Medical School, 303 East Chicago Ave., Chicago, IL 60611. 1046-6673/050 1-0047$03.00/0 Journal of the Americon Society of Nephrology Copyright C 1994 by the American society of Nephrology significantly affected posttranslational modifications of PG. The HGF preferentially enhanced the synthesis of heparan sulfate-PG in both cell types, whereas TGF- 31 disproportionately stimulated the synthesis of chondroitin sulfate-PG. These data indicate that HGF and TGF- 31 selectively modulate the synthesis of PG derived from ADPKD cells, whereas the GF differen- tially influence the posttranslational modifications of PG in both the NK and ADPKD cells, henceforth, sug- gesting a potential role of GF in the pathogenesis of PKD. Key Words: Growth factors. proteoglycans. polycystic kidney disease P olycystic kidney disease (PKD) is characterized by progressive and segmental dilation of the renal tubules accompanied by alterations of the ex- tracellular matrix (ECM), aberrant tubular cell growth, and fluid accumulation (1-4). The changes in ECM are confined to the tubular basement mem- brane (TBM) and intenstitium and have been reported in various human and experimental forms of PKD (5-7). The TBM are thickened and laminated, and the biochemical alterations are reflected in the in- creased expression of type IV collagen and laminin (8) and the decreased expression of sulfated proteo- glycans (6). The de novo synthesized sulfated PG have a decreased content of heparan sulfate but an increased proportion of chondroitin sulfate (9,10). The PG are of relatively high molecular weight and exhibit reduced charge-density characteristics as a result of the decreased sulfation of glycosaminogly- can (GAG) chains (9,10). These heavily glycosylated glycopnoteins, i.e. , PG. are known to play a significant role in cell-cell and cell-ECM interactions, in morphogenesis and onga- nogenesis, and in cell proliferation and specific cel- lulan gene expression ( 11 - 1 3). Conceivably, their de- creased expression in the TBM probably leads to the aberrant ECM organization of the TBM and defective interactions with the overlying cells. These defects in the TBM and in the cellular interactions may ultimately be responsible for the cystic dilation of tubules in PKD. The expression of these morphogenetic regulators,