The RIP1-kinase inhibitor necrostatin-1 prevents osmotic nephrosis and contrast-induced AKI in mice.

Abstract

The pathophysiology of contrast-induced AKI (CIAKI) is incompletely understood due to the lack of an appropriate in vivo model that demonstrates reduced kidney function before administration of radiocontrast media (RCM). Here, we examine the effects of CIAKI in vitro and introduce a murine ischemia/reperfusion injury (IRI)-based approach that allows induction of CIAKI by a single intravenous application of standard RCM after injury for in vivo studies. Whereas murine renal tubular cells and freshly isolated renal tubules rapidly absorbed RCM, plasma membrane integrity and cell viability remained preserved in vitro and ex vivo, indicating that RCM do not induce apoptosis or regulated necrosis of renal tubular cells. In vivo, the IRI-based CIAKI model exhibited typical features of clinical CIAKI, including RCM-induced osmotic nephrosis and increased serum levels of urea and creatinine that were not altered by inhibition of apoptosis. Direct evaluation of renal morphology by intravital microscopy revealed dilation of renal tubules and peritubular capillaries within 20 minutes of RCM application in uninjured mice and similar, but less dramatic, responses after IRI pretreatment. Necrostatin-1 (Nec-1), a specific inhibitor of the receptor-interacting protein 1 (RIP1) kinase domain, prevented osmotic nephrosis and CIAKI, whereas an inactive Nec-1 derivate (Nec-1i) or the pan-caspase inhibitor zVAD did not. In addition, Nec-1 prevented RCM-induced dilation of peritubular capillaries, suggesting a novel role unrelated to cell death for the RIP1 kinase domain in the regulation of microvascular hemodynamics and pathophysiology of CIAKI.

• Authors: Andreas Linkermann, Jan-Ole Heller, Agnes Prókai, Joel M Weinberg, Federica De Zen, Nina Himmerkus, Attila J Szabó, Jan H Bräsen, Ulrich Kunzendorf, Stefan Krautwald
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 24 Issue 10 Pg. 1545-57 (Oct 2013) ISSN: 1533-3450 [Electronic] United States
• PMID: 23833261 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Contrast Media
• Imidazoles
• Indoles
• necrostatin-1
• Receptor-Interacting Protein Serine-Threonine Kinases

Topics

• Acute Kidney Injury (chemically induced, prevention & control)
• Animals
• Cell Death
• Cell Line
• Contrast Media (toxicity)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Imidazoles (pharmacology, therapeutic use)
• Indoles (pharmacology, therapeutic use)
• Kidney Tubules (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Nephrosis (chemically induced, prevention & control)
• Receptor-Interacting Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Reperfusion Injury (complications)