Heterogeneous metabolism and toxicity of 4-pentenoate along the dog nephron.

4-Pentenoate (4P) is a short-chain fatty acid which causes a complete renal Fanconi syndrome. We have examined the mechanism of 4P toxicity along the nephron after a prolonged (30 min) exposition of isolated renal tubular segments to this agent. In proximal tubules, 4P inhibited the activity of alpha-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and beta-oxidation, but not in thick ascending limb or inner medullary collecting duct tubules in suspension. These proximal effects were accompanied by a marked oxidation of the proximal redox state, with a fall in the tissue respiration and a low content of ATP. The acetyl-CoA content of proximal tubules was simultaneously reduced. Butyrate, acetate, hexanoate or octanoate did not exert these effects. In proximal tubules the metabolism of 4P led to the tissue accumulation of 3-keto-4-pentenoyl-CoA, a known unspecific inhibitor of metabolic oxidation. This metabolite was not detectable in thick ascending limbs which metabolized 4P rapidly. No metabolism of 4P was noted in collecting ducts. We conclude that beta-oxidation probably differs in proximal and thick ascending limb tubules, allowing 4P metabolism to exert a specific toxicity in proximal tubules. A selective proximal defect in energy metabolism probably explains the Fanconi syndrome observed with exposition to 4P.