Therapeutic targeting of the mitochondrial dysfunction in... : Current Opinion in Critical Care (original) (raw)

RENAL SYSTEM: Edited by Ravindra L. Mehta

Therapeutic targeting of the mitochondrial dysfunction in septic acute kidney injury

Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

Correspondence to Samir M. Parikh, MD, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, RN 280C, Boston, MA 02215, USA. Tel: +1 617 667 5813; fax: +1 617 667 2646; e-mail: [email protected]

Abstract

Purpose of review

Acute kidney injury (AKI) is a common and serious complication of severe sepsis. No targeted therapies exist for sepsis-associated AKI, suggesting a pressing need for elucidation of the underlying pathogenic mechanisms.

Recent findings

Emerging studies of human and experimental septic AKI kidneys have affirmed the longstanding observation that cell death in the tubule is uncommon despite often severe impairment of filtration. Rather than cell death, there appears to be widespread sublethal injury to tubular epithelial mitochondria. These organelles efficiently harness energy through controlled oxidation of metabolic fuels, they house pro-apoptotic proteins, and they produce reactive oxygen species. Derangement in one or more of these functions may contribute to the large reduction in renal function in septic AKI despite only scant cell death. In experimental septic AKI, molecular markers of mitochondrial biogenesis and function – whose renal expression dips during injury – rebound to normal levels as kidney function improves. Results from knockout mice suggest that restoration of mitochondrial function within the nephron may be critical to functional recovery.

Summary

Recent findings from human and experimental septic AKI studies strongly implicate the mitochondrion as an important target for sublethal kidney injury. Stimulating the natural pathways through which mitochondrial function is normally recovered following sepsis represents a promising strategy for the development of novel therapies.