title: Selective stabilization of HIF-1α in renal tubular cells by 2-oxoglutarate analogues.
abstract: The role of proximal versus distal tubular injury in the pathogenesis of acute kidney injury (AKI) is debatable. Inhibition of prolyl hydroxylases that regulate the degradation of hypoxia-inducible transcription factors (HIFs) is a promising therapeutic approach to optimize energy preservation under hypoxia and has successfully been applied to protect kidney structure and function in AKI models. Presently used prolyl hydroxylase inhibitors are lipophilic 2-oxoglutarate analogues (2OGAs) that are widely taken up in cells of most organs. Given the selective expression of organic anion transporters (OATs) in renal proximal tubular cells, we hypothesized that hydrophilic 2OGAs can specifically target proximal tubular cells. We found that cellular hydrophilic 2OGAs uptake depended on OATs and largely confined to the kidney, where it resulted in activation of HIF target genes only in proximal tubular cells. When applied in ischemia-reperfusion experiments, systemically active 2OGA preserved kidney structure and function, but OAT1-transported 2OGA was not protective, suggesting that HIF stabilization in distal tubular rather than proximal tubular cells and/or nontubular cells mediates protective effects. This study provides proof of concept for selective drug targeting of proximal tubular cells on the basis of specific transporters, gives insights into the role of different nephron segments in AKI pathophysiology, and may offer options for long-term HIF stabilization in proximal tubules without confounding effects of erythropoietin induction in peritubular cells and unwarranted extrarenal effects.
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schley
authors.forename: Bernd
authors.initials: B
authors.lastname: Klanke
authors.forename: Johannes
authors.initials: J
authors.lastname: Schödel
authors.forename: Sven
authors.initials: S
authors.lastname: Kröning
authors.forename: Gazi
authors.initials: G
authors.lastname: Türkoglu
authors.forename: Andreas
authors.initials: A
authors.lastname: Beyer
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Hagos
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Birgitta C
authors.initials: BC
authors.lastname: Burckhardt
authors.forename: Nicolai
authors.initials: N
authors.lastname: Burzlaff
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
mesh_terms: D019342:Acetic Acid / Q000737:chemistry / Q000494:pharmacology; D058186:Acute Kidney Injury / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002469:Cell Separation; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007511:Ischemia / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D019194:Ischemic Preconditioning; D007656:Ketoglutaric Acids / Q000737:chemistry* / Q000494:pharmacology*; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000600:Amino Acids, Dicarboxylic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D027362:Organic Anion Transport Protein 1; D011725:Pyridines; C055293:2,4-pyridinedicarboxylic acid; D019342:Acetic Acid; C040947:oxalylglycine