CALCIUM-OXALATE MONOHYDRATE CRYSTALS STIMULATE GENE-EXPRESSION IN RENAL EPITHELIAL-CELLS

Primary or secondary hyperoxaluria is associated with calcium oxalate nephrolithiasis, interstitial fibrosis and progressive renal insuffici ency. Monolayer cultures of nontransformed monkey kidney epithelial ce lls (BSC-I line) and calcium oxalate monohydrate (COM) crystals were u sed as a model system to study cell responses to crystal interactions that might occur in the nephrons of patients during periods of hyperox aluria. To determine if COM crystals signal a change in gene expressio n, Northern blots were prepared from total renal cellular RNA after th e cells were exposed to crystals. Tile immediate early genes c-myc, EG R-1, and Nur-77 were induced at one hour. At two to six hours stimulat ed expression of the genes encoding plasminogen activator inhibitor (P AI-1) and platelet-derived growth factor (PDGF)-A chain was detected, but constitutive expression of urokinase-type plasminogen activator (u -PA) was not altered. Expression of connective tissue growth factor (C TGF) was induced at one hour and persisted up to 24 hours. The stimula tion of gene expression by COM crystals was relatively crystal- and re nal cell-type specific. Thus the interaction of kidney epithelial cell s with COM crystals alters expression of genes that encode three class es of proteins: transcriptional activators, a regulator of extracellul ar matrix (ECM), and growth factors. Activation of PAI-1 gene expressi on without a change in u-PA favors accumulation of ECM proteins, as do es increased expression of PDGF and CTGF which can also stimulate fibr oblast proliferation in a paracrine manner. These results suggest that COM crystal-mediated stimulation of specific genes in renal tubular c ells may contribute to the development of interstitial fibrosis in hyp eroxaluric states.