Late Intervention with the Small Molecule BB3 Mitigates Post-ischemic Kidney Injury

Authors

Prakash Narayan, Bin Duan, Kai Jiang, Jingsong Li, Latha Paka, Michael Yamin, Scott L. Friedman, Matthew Ryan Weir, Itzhak D. Goldberg

Abstract

Ischemia-reperfusion-mediated acute kidney injury can necessitate renal replacement therapy and is a major cause of morbidity and mortality. We have identified BB3, a small molecule, which when first administered at 24 hr following renal ischemia in rats, improved survival, augmented urine output and reduced the increase in serum creatinine and blood urea nitrogen. Compared with control kidneys, the kidneys of BB3-treated animals exhibited reduced levels of kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, reduced tubular apoptosis and acute tubular necrosis but enhanced tubular regeneration. Consistent with its hepatocyte growth factor-like mode of action, BB3 treatment promoted phosphorylation of renal cMet and Akt and upregulated renal expression of the survival protein Bcl-2. These data suggest that the kidney is amenable to pharmacotherapy even 24 hr after ischemia-reperfusion, and that activation of the hepatocyte growth factor signaling pathway with the small molecule BB3 confers interventional benefit late into ischemia-reperfusion injury. These data, formed, in part, the basis for use of BB3 in a clinical trial in kidney recipients presenting with delayed graft function.