Altered cholesterol localization and caveolin expression during the evolution of acute renal failure.
BACKGROUND
Renal cortical/proximal tubule cholesterol accumulation, with preferential localization within plasma membrane "detergent resistant microdomains" (DRMs: rafts/caveolae), is a hallmark of the maintenance phase of acute renal failure (ARF). This study addressed two related issues: (1) Are maintenance-phase cholesterol increases accompanied by an up-regulation of caveolin, a DRM/caveolar-associated cholesterol binding protein? (2) Is DRM cholesterol/caveolin homeostasis acutely altered during the induction phase of ARF?


METHODS
Mouse kidneys were subjected to ischemia +/- reperfusion (I/R) followed by assessment of cholesterol DRM partitioning. Acute cell injury effects on potential caveolin release from isolated proximal tubules or into urine also were assessed. Finally, renal cortical/isolated proximal tubule caveolin levels were determined 18 hours after I/R or myoglobinuric ARF.


RESULTS
Acute ischemia causes a rapid shift of cholesterol into cortical DRMs (>22%). Cholesterol migration into DRMs also was observed in ATP-depleted cultured proximal tubule (HK-2) cells. Acute hypoxic or toxic tubule injury induced plasma membrane caveolin release (Western blot). By the maintenance phase of ARF, marked renal cortical/proximal tubule caveolin increases resulted.


CONCLUSIONS
Acute proximal tubular injury damages caveolar/DRM structures, as determined by cholesterol maldistribution and caveolin release. Post-injury, there is a dramatic up-regulation of renal cortical/proximal tubule caveolin, suggesting an increased caveolar mass. These findings indicate, to our knowledge for the first time, that dysregulation of caveolae/raft microdomain expression is a correlate of, and potential participant in, the induction and maintenance phases of ischemic and toxic forms of experimental ARF.
Zager
Richard A
RA
Department of Medicine, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. dzager@fhcr.org
Johnson
Ali
A
Hanson
Sherry
S
dela Rosa
Vivian
V
D058186:Acute Kidney Injury / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D051242:Caveolin 1; D022461:Caveolins / Q000032:analysis / Q000096:biosynthesis* / Q000652:urine; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002784:Cholesterol / Q000032:analysis*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009212:Myoglobinuria / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism
C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D000255:Adenosine Triphosphate; D002784:Cholesterol