title: Renal 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase Is an Important Determinant of AKI Severity after Ischemia-Reperfusion.
abstract: A positional isomer of 3',5'-cAMP, 2',3'-cAMP, is produced by kidneys in response to energy depletion, and renal 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) metabolizes 2',3'-cAMP to 2'-AMP; 2',3'-cAMP is a potent opener of mitochondrial permeability transition pores (mPTPs), which can stimulate autophagy. Because autophagy protects against AKI, it is conceivable that inhibition of CNPase protects against ischemia-reperfusion (IR) -induced AKI. Therefore, we investigated renal outcomes, mitochondrial function, number, area, and autophagy in CNPase-knockout (CNPase(-/-)) versus wild-type (WT) mice using a unique two-kidney, hanging-weight model of renal bilateral IR (20 minutes of ischemia followed by 48 hours of reperfusion). Analysis of urinary purines showed attenuated metabolism of 2',3'-cAMP to 2'-AMP in CNPase(-/-) mice. Neither genotype nor IR affected BP, heart rate, urine volume, or albumin excretion. In WT mice, renal IR reduced (14)C-inulin clearance (index of GFR) and increased renal vascular resistance (measured by transit time nanoprobes) and urinary excretion of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. IR did not affect these parameters in CNPase(-/-) mice. Histologic analysis revealed that IR induced severe damage in kidneys from WT mice, whereas histologic changes were minimal after IR in CNPase(-/-) mice. Measurements of renal cardiolipin levels, citrate synthase activity, rotenone-sensitive NADH oxidase activity, and proximal tubular mitochondrial and autophagosome area and number (by transmission electron microscopy) indicted accelerated autophagy/mitophagy in injured CNPase(-/-) mice. We conclude that CNPase deletion attenuates IR-induced AKI, in part by accelerating autophagy with targeted removal of damaged mitochondria.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; edj@pitt.edu.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: Menshikova
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Zaichuan
authors.initials: Z
authors.lastname: Mi
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Verrier
authors.affiliation: Department of Neuroscience, University of Connecticut School of Medicine, Farmington, Connecticut; and.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bansal
authors.affiliation: Safar Center for Resuscitation Research and Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Keri
authors.initials: K
authors.lastname: Janesko-Feldman
authors.affiliation: Safar Center for Resuscitation Research and Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Travis C
authors.initials: TC
authors.lastname: Jackson
authors.affiliation: Safar Center for Resuscitation Research and Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
mesh_terms: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000502:physiology*; D058186:Acute Kidney Injury / Q000201:enzymology* / Q000209:etiology; D000818:Animals; D005260:Female; D007668:Kidney / Q000098:blood supply; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000150:complications; D012720:Severity of Illness Index
chemical_list: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase
keywords: acute renal failure; cyclic AMP; electron microscopy; ischemia-reperfusion; mitochondria; renal ischemia