Renal tubular triglyercide accumulation following endotoxic, toxic, and ischemic injury

Background. Cholesterol accumulates in renal cortical proximal tubules in response to diverse forms of injury or physiologic stress. However, the fate of triglycerides after acute renal insults is poorly defined. This study sought new insights into this issue. Methods. CD-1 mice were subjected to three diverse models of renal stress: (1) endotoxemia [Escherichia coli lipopolysaccharide (LPS), injection]; (2) ischemia/reperfusion (I/R); or (3) glycerol-induced rhabdomyolysis. Renal cortical, or isolated proximal tubule, triglyceride levels were measured similar to18 hours later. To gain mechanistic insights, triglyceride levels were determined in (1) proximal tubules following exogenous phospholipase A(2) (PLA(2)) treatment; (2) cultured HK-2 cells after mitochondrial blockade (antimycin A)+/-serum; or (3) HK-2 cells following "septic" (post-LPS) serum, or exogenous fatty acid (oleate) addition. Results. Each form of in vivo injury evoked three- to four-fold triglyceride increases in renal cortex and/or proximal tubules. PLA(2) treatment of proximal tubules evoked acute, dose-dependent, triglyceride formation. HK-2 cell triglyceride levels rose with antimycin A. With serum present, antimycin A induced an exaggerated triglyceride loading state (vs. serum alone or antimycin A alone). "Septic" serum stimulated HK-2 triglyceride formation (compared to control serum). Oleate addition caused striking HK-2 cell triglyceride accumulation. Following oleate washout, HK-2 cells were sensitized to adenosine triphosphate (ATP) depletion or oxidant attack. Conclusion. Diverse forms of renal injury induce dramatic triglyceride loading in proximal tubules/renal cortex, suggesting that this is a component of a cell stress response. PLA(2) activity, increased triglyceride/triglyceride substrate (e.g., fatty acid) uptake, and possible systemic cytokine (e.g., from LPS) stimulation, may each contribute to this result. Finally, in addition to being a marker of prior cell injury, accumulation of triglyceride (or of its constituent fatty acids) may predispose tubules to superimposed ATP depletion or oxidant attack.