title: Late intervention with the small molecule BB3 mitigates postischemic kidney injury.
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 h after 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, and 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 h after ischemia-reperfusion and that activation of the hepatocyte growth factor signaling pathway with the small molecule BB3 confers interventional benefits late into ischemia-reperfusion injury. These data formed, in part, the basis for the use of BB3 in a clinical trial in kidney recipients presenting with delayed graft function.
authors.affiliation: Department of Preclinical Research, Angion Biomedica Corporation, New York, New York; pnarayan@angion.com.
authors.forename: Prakash
authors.initials: P
authors.lastname: Narayan
authors.affiliation: Department of Preclinical Research, Angion Biomedica Corporation, New York, New York;
authors.forename: Bin
authors.initials: B
authors.lastname: Duan
authors.affiliation: Department of Preclinical Research, Angion Biomedica Corporation, New York, New York;
authors.forename: Kai
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Preclinical Research, Angion Biomedica Corporation, New York, New York;
authors.forename: Jingsong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Preclinical Research, Angion Biomedica Corporation, New York, New York;
authors.forename: Latha
authors.initials: L
authors.lastname: Paka
authors.affiliation: Department of Preclinical Research, Angion Biomedica Corporation, New York, New York;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Yamin
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York; and.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland Medical Center, Baltimore, Maryland.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Weir
authors.affiliation: Department of Preclinical Research, Angion Biomedica Corporation, New York, New York;
authors.forename: Itzhak D
authors.initials: ID
authors.lastname: Goldberg
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*
chemical_list: D017228:Hepatocyte Growth Factor
keywords: ischemia-reperfusion; kidney; small molecule; therapy