GLYCINE ATTENUATES FANCONI SYNDROME INDUCED BY MALEATE OR IFOSFAMIDE IN RATS

It has become widely recognized that glycine (Gly) depletion predispos es isolated proximal tubules (PT) to necrotic cell damage induced by d iverse insults and that Gly replacement in vitro is highly cytoprotect ive. However, the effectiveness of supplementation with Cry in vivo, w here blood and tissue Gly normally are maintained at high levels, is i ncompletely defined. Our aim was to assess whether: (a) supplementatio n of Gly in drinking water of rats would attenuate the proximal tubule damage and the Fanconi syndrome (FS) induced by maleate (Mall, a clas sical proximal tubule toxin, or ifosfamide (IFO), an antineoplastic dr ug; and Ib) to explore the mechanisms responsible for such effects, si nce Gly supplementation might be especially beneficial in treating the FS, where the kidney tends to waste amino acids. Rats received daily injection of Mal (2 mmol/kg) for two days without or with oral supplem entation of 2% Gly. IFO, 50 mg/kg, was injected daily for five days wi thout or with oral Gly. Control rats were injected with saline, withou t or with oral Gly. The results demonstrated that both Mal and IFO ind uced a FS characterized by wasting of amino and organic acids, glucose , and electrolytes, along with elevated plasma creatinine (Cm) and BUN , and decreased Cm clearance rate. Light microscopy revealed a necroti c lesion in the proximal tubules of the Mal group, but no necrosis aft er IFO. Gly strongly ameliorated the severity of renal necrosis and/or dysfunction induced by Mal or IFO, with significant decreases in tota l and fractional excretion of Na+, K+, PO43- and glucose, decreased pl asma BUN and Crn, and increased Crn clearance. Analysis of freeze-clam ped cortical tissue showed substantial depletion of [Gly], [ATP] and [ GSH] along with increased GSSG in Mal or IFO groups and correction of [Gly] and [ATP] with Gly supplementation, but no improvement with Gly of reduced gluthatione [GSH] or the ratio of reduced to oxidized gluth atione (GSH/GSSG). P-31-NMR analysis of the renal cortex indicated a d ecrease in Pi and various membrane phospholipids in Mal and IFO rats a nd prevention of this damage with Gly. These observations demonstrate that oral supplementation of Gly can provide protection against Mal or IFO-induced renal tubular cell dysfunction and structural damage. The lack of effect on glutathione oxidation and depletion suggests an act ion distal to toxin uptake and intracellular interactions, which is si milar to the characteristics of Gly cytoprotection against diverse ins ults in vitro. The results also suggest modification by Gly of the pri mary toxicity of the agents and effects on phospholipid synthesis that could contribute to repair.