PPARα protects proximal tubular cells from acute fatty acid toxicity

Fatty acids bound to albumin are filtered through glomeruli, reabsorbed by proximal tubular epithelial cells, and metabolized. Because albumin serves as a carrier, an increase in delivery of fatty acids to the proximal tubule may occur in proteinuric states, possibly leading to toxic effects. At present, the contribution of fatty acids to tubulointerstitial damage and the mechanisms underlying this toxicity remain unclear. We recently found that the transcription factor peroxisome proliferator-activated receptor a (PPAR alpha) regulates fatty acid metabolism in proximal tubules, so we tested its role in tubular damage under proteinuric conditions. We induced protein-overload nephropathy in Ppara-null or wildtype (WT) mice by injecting fatty acids bound to BSA. Ppara-null mice exhibited greater renal dysfunction from severe proximal tubular injury than WT mice. Kidneys from Ppara-null mice injected with albumin alone showed little injury. Acute tubular injury was associated with deranged fatty acid homeostasis, increased oxidative stress, increased apoptosis, and activation of NF kappa B signaling. These results suggest a role for fatty acids in proteinuria-associated tubular toxicity, as well as a protective role for PPARa. Modulation of PPARa may be a future therapeutic option for tubular toxicity from fatty acids.