title: A PTBA small molecule enhances recovery and reduces postinjury fibrosis after aristolochic acid-induced kidney injury.
abstract: Phenylthiobutanoic acids (PTBAs) are a new class of histone deacetylase (HDAC) inhibitors that accelerate recovery and reduce postinjury fibrosis after ischemia-reperfusion-induced acute kidney injury. However, unlike the more common scenario in which patients present with protracted and less clearly defined onset of renal injury, this model of acute kidney injury gives rise to a clearly defined injury that begins to resolve over a short period of time. In these studies, we show for the first time that treatment with the PTBA analog methyl-4-(phenylthio)butanoate (M4PTB) accelerates recovery and reduces postinjury fibrosis in a progressive model of acute kidney injury and renal fibrosis that occurs after aristolochic acid injection in mice. These effects are apparent when M4PTB treatment is delayed 4 days after the initiating injury and are associated with increased proliferation and decreased G2/M arrest of regenerating renal tubular epithelial cells. In addition, there is reduced peritubular macrophage infiltration and decreased expression of the macrophage chemokines CX3Cl1 and CCL2. Since macrophage infiltration plays a role in promoting kidney injury, and since renal tubular epithelial cells show defective repair and a marked increase in maladaptive G2/M arrest after aristolochic acid injury, these findings suggest M4PTB may be particularly beneficial in reducing injury and enhancing intrinsic cellular repair even when administered days after aristolochic acid ingestion.
authors.affiliation: Vanderbilt Univ. Medical Center, Dept. of Medicine, Div. of Nephrology, S3223 Medical Center North, 1161 21st Ave. South, Nashville, TN 37232. mark.de.caestecker@vanderbilt.edu.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Novitskaya
authors.forename: Lee
authors.initials: L
authors.lastname: McDermott
authors.forename: Ke Xin
authors.initials: KX
authors.lastname: Zhang
authors.forename: Takuto
authors.initials: T
authors.lastname: Chiba
authors.forename: Paisit
authors.initials: P
authors.lastname: Paueksakon
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hukriede
authors.forename: Mark P
authors.initials: MP
authors.lastname: de Caestecker
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D034341:Aristolochic Acids / Q000494:pharmacology; D002087:Butyrates / Q000032:analysis / Q000494:pharmacology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy / Q000517:prevention & control; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D038602:Mice, Biozzi; D015427:Reperfusion Injury / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D013440:Sulfides / Q000032:analysis / Q000494:pharmacology*
chemical_list: C549619:4-(phenylthio)butanoic acid; D034341:Aristolochic Acids; D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D013440:Sulfides; C000228:aristolochic acid I
keywords: HDAC inhibitor; aristolochic acid; fibrosis; kidney injury