Renal cortical cholesterol accumulation is an integral component of the systemic stress response

Abstract

Background: Direct tubular injury (such as ischemia or myohemoglobinuria) increases renal cortical cholesterol content. This study explored whether systemic forms of stress (such as heat shock or sepsis) can trigger renal cholesterol accumulation, and if so, whether increased 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) expression might be involved.

Methods: Male CD-1 mice were subjected to glycerol-induced myohemoglobinuria (MH), systemic heat shock (HS), or E. coli sepsis. Free cholesterol (FC), cholesteryl esters (CE), and HMGCR (Western blot) levels were assessed 18 hours later. Statin effects on renal cholesterol levels and on the severity of MH-acute renal failure (ARF) were also determined.

Results: Sepsis and HS each induced dramatic FC and CE increments, comparable to those observed with myohemoglobinuria, and without inducing acute tubular necrosis (ATN). Part of the cholesterol increments was localized within plasma membrane (detergent resistant) microdomains (for example, rafts/caveolae). HS and MH each increased renal HMGCR, as well as HS protein (HSP-72) expression. Oxidant stress (Fe) imposed on cultured proximal tubule (HK-2) cells also enhanced HMGCR content. Conversely, sepsis did not raise renal HMGCR or HSP-72 levels. Statin therapy decreased the severity of MH-ARF and renal cholesterol content. However, this appeared to arise from a statin-mediated decrease in glycerol-induced extrarenal tissue damage (myolysis/LDH release).

Conclusions: Cholesterol appears to be a renal 'acute phase reactant' with tissue levels increasing with either systemic stress (such as, heat shock, sepsis), or direct tissue damage (such as ATN). Increased HMGCR expression can contribute to this result. Mechanisms other than HMGCR induction also can mediate stress-induced cholesterol increments (for example, in the case of sepsis), and statins can mitigate MH-ARF. However, systemic anti-inflammatory effects, rather than a primary renal action, appear more likely to be involved.