Acute renal injury causes accumulation of free and esterified
cholesterol (FC, CE) in proximal tubules, mediated, at least in part, by increased
cholesterol synthesis. Normally, this would trigger compensatory mechanisms such as increased efflux and decreased influx to limit or reverse the
cholesterol overload state. This study sought to determine the integrity of these compensatory pathways following acute renal damage.
Rhabdomyolysis-induced
acute renal failure was induced in mice by
glycerol injection. Normal mice served as controls. After 18 hours, BUN levels and renal cortical FC/CE content were determined. Expression of ABCA-1 and SR-B1 (
cholesterol efflux
proteins) were assessed by Western blot. Renal cortical
LDL receptor (
LDL-R; a
cholesterol importer) regulation was gauged by quantifying its
mRNA. To obtain proximal tubule cell-specific data, the impact of
oxidant (Fe) stress on cultured HK-2 cell
LDL-R, SR-B1, and ABCA-1
proteins and their mRNAs (versus controls) was assessed.
Glycerol evoked marked
azotemia and striking FC/CE increments (44%, 384%, respectively). Paradoxically, renal cortical SR-B1 and ABCA-1
protein reductions and
LDL-R
mRNA increments resulted. Fe-induced injury suppressed HK-2 cell SR-B1, ABCA-1, and their mRNAs.
LDL-R
protein rose with the in vitro Fe challenge. Renal tubular cell injury causes dysregulation of SR-B1, ABCA-1, and
LDL-R
protein expression, changes which should contribute to a
cholesterol overload state. Reductions in HK-2 cell SR-B1 and ABCA-1 mRNAs and increases in renal cortical
LDL-R
mRNA imply that this dysregulation reflects, at least in part, altered genomic/transcriptional events.