Renal cholesterol accumulation - A durable response after acute and subacute renal insults

Proximal tubular cholesterol levels rise within 18 hours of diverse forms o f acute renal tubular injury (eg, myoglobinuria, ischemia/reperfusion, urin ary tract obstruction). These increments serve to protect against further b outs of tubular attack (so-called "acquired cytoresistance"). Whether these cholesterol increments are merely transitory, or persist into the maintena nce phase of acute renal failure (ARF), has not been previously defined. Fu rthermore, whether subacute/insidious tubular injury [eg, cyclosporine A (C SA), tacrolimus toxicity], nontubular injury (eg, acute glomerulonephritis) , or physiological stress (eg, mild dehydration) impact renal cholesterol h omeostasis have not been addressed. This study sought to resolve these issu es. Male CD-I mice were subjected to glycerol-induced ARF. Renal cortical-f ree cholesterol (FC) and cholesterol ester (CE) levels were determined 3, 5 , 7, or 14 days later, and the values contrasted to prevailing blood-urea n itrogen concentrations. The impact of 40 minutes of unilateral renal ischem ia plus reflow (3 to 6 days) on mouse cortical FC/CE content was also asses sed. Additionally, FC/CE levels were measured in rat renal cortex either 10 days after CSA or tacrolimus therapy, or 48 hours after induction of nephr otoxic serum nephritis. Finally, the impact of overnight dehydration on mou se renal cortical/medullary FC/CE profiles was determined. Compared to sham -treated animals, glycerol, CSA, tacrolimus, ischemia-reperfusion, and neph rotoxic serum each induced dramatic CE +/- FC elevations, rising as much as 10x control values. In the glycerol model, striking correlations (r less t han or equal to 0.99) between FC/CE and blood-urea nitrogen levels were obs erved. The FC/CE increases were specific to damaged kidney (glycerol did no t raise hepatic FC/CE; unilateral renal ischemia did not alter contralatera l renal FC/CE levels). Overnight dehydration raised renal CE levels, most n otably in the medulla. Conclusions: FC/CE accumulation is a hallmark of the maintenance phase of ischemic and nephrotoxic ARF, and can reflect its sev erity. That cholesterol accumulation can result from glomerular injury and dehydration suggests that it is a generic renal stress response, with poten tial relevance extending beyond just the phenomenon of acquired cytoresista nce.