Oxalate-induced changes in the viability and growth of human renal epithelial cells

Previous studies on the porcine renal epithelial LLC-PK1 cell Line demonstr ated that oxalale exposure produces concentration-dependent effects on rena l cell growth and viability via process(es) involving free radicals. The pr esent studies were conducted to determine whether these findings could be e xtended to a renal proximal tubular epithelial cell line derived from the h uman kidney. These studies examined oxalate-induced changes in membrane int egrity after short-term exposure (4 h) and changes in cell survival after l onger-term exposure (24 to 72 h). Oxalate-induced changes were: also assess ed in the expression of two genes: egr-1, a zinc-finger transcription facto r, and osteopontin, a protein associated with tissue remodeling. The presen t studies also determined whether oxalate-induced changes in either cell vi ability or gene expression depended on free radicals. Oxalate at a concentr ation greater than or equal to 175 mu M (free) produced membrane damage wit hin 4 h. This effect was inhibited by Mn(III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP), a superoxide dismutase mimetic, but not by N-acetyl c ysteine, a glutathione precursor, or by deferoxamine, an iron chelator. Acu te oxalate-induced injury was followed by cell loss within 24 h, an effect maintained at 48 and 72 hat high concentrations of oxalate. Oxalate also pr omoted DNA synthesis. This mitogenic effect offset cell loss at lower oxala te concentrations (88 mu M) leading to a small but significant increase in cell number at 72 h. Treatment with oxalate also increased expression of eg r-1 mRNA within 1 h, a response that was attenuated by MnTMPyP; oxalate tre atment for 8 h also increased abundance of osteopontin mRNA. These studies suggest that oxalate exposure produces changes in human renal cell growth a nd viability via a process(es) dependent on reactive oxygen intermediates. Such changes may play a role in the development and/or progression of renal disease via generation of reactive oxygen intermediates.