title: cGMP-selective phosphodiesterase inhibitors stimulate mitochondrial biogenesis and promote recovery from acute kidney injury.
abstract: Recent studies demonstrate that mitochondrial dysfunction is a mediator of acute kidney injury (AKI). Consequently, restoration of mitochondrial function after AKI may be key to the recovery of renal function. Mitochondrial function can be restored through the generation of new, functional mitochondria in a process called mitochondrial biogenesis (MB). Despite its potential therapeutic significance, very few pharmacological agents have been identified to induce MB. To examine the efficacy of phosphodiesterase (PDE) inhibitors (PDE3: cAMP and cGMP activity; and PDE4: cAMP activity) in stimulating MB, primary cultures of renal proximal tubular cells (RPTCs) were treated with a panel of inhibitors for 24 hours. PDE3, but not PDE4, inhibitors increased the FCCP-uncoupled oxygen consumption rate (OCR), a marker of MB. Exposure of RPTCs to the PDE3 inhibitors, cilostamide and trequinsin, for 24 hours increased peroxisome proliferator-activated receptor γ coactivator-1α, and multiple mitochondrial electron transport chain genes. Cilostamide and trequinsin also increased mRNA expression of mitochondrial genes and mitochondrial DNA copy number in mice renal cortex. Consistent with these experiments, 8-Br-cGMP increased FCCP-uncoupled OCR and mitochondrial gene expression, whereas 8-Br-cAMP had no effect. The cGMP-specific PDE5 inhibitor sildenafil also induced MB in RPTCs and in vivo in mouse renal cortex. Treatment of mice with sildenafil after folic acid-induced AKI promoted restoration of MB and renal recovery. These data provide strong evidence that specific PDE inhibitors that increase cGMP are inducers of MB in vitro and in vivo, and suggest their potential efficacy in AKI and other diseases characterized by mitochondrial dysfunction and suppressed MB.
authors.affiliation: Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina; and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Whitaker
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Wills
authors.forename: L Jay
authors.initials: LJ
authors.lastname: Stallons
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005492:Folic Acid; D015870:Gene Expression / Q000187:drug effects; D006397:Hematinics; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics; D010101:Oxygen Consumption / Q000187:drug effects; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D006397:Hematinics; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate; D005492:Folic Acid; D000068677:Sildenafil Citrate; D015105:3',5'-Cyclic-AMP Phosphodiesterases
references.citation: Anal Biochem. 2010 Sep 1;404(1):75-81
references.pmid: 20465991
references.citation: Am J Physiol. 1995 Nov;269(5 Pt 1):C1317-25
references.pmid: 7491924
references.citation: Am J Physiol Renal Physiol. 2013 Apr 15;304(8):F1099-104
references.pmid: 23364806
references.citation: Cell. 1999 Jul 9;98(1):115-24
references.pmid: 10412986
references.citation: J Clin Invest. 2009 May;119(5):1275-85
references.pmid: 19349686
references.citation: Kidney Int. 2012 Feb;81(4):338-40
references.pmid: 22289794
references.citation: Anal Chim Acta. 2012 May 21;727:8-12
references.pmid: 22541816
references.citation: Toxicology. 2009 Mar 29;257(3):137-43
references.pmid: 19152827
references.citation: Am J Physiol Renal Physiol. 2010 Jul;299(1):F199-206
references.pmid: 20410216
references.citation: Antioxid Redox Signal. 2011 Dec 1;15(11):2837-54
references.pmid: 21767162
references.citation: J Pharmacol Exp Ther. 2008 May;325(2):536-43
references.pmid: 18267976
references.citation: Ann N Y Acad Sci. 2012 Oct;1271:110-7
references.pmid: 23050972
references.citation: Antioxid Redox Signal. 2013 Jul 20;19(3):240-2
references.pmid: 23432475
references.citation: J Am Soc Nephrol. 2011 Mar;22(3):431-6
references.pmid: 21355058
references.citation: J Clin Invest. 2011 Oct;121(10):4003-14
references.pmid: 21881206
references.citation: Circulation. 2013 May 14;127(19):1932-4
references.pmid: 23589023
references.citation: J Am Coll Cardiol. 2013 Feb 12;61(6):599-610
references.pmid: 23219298
references.citation: Pharmacol Rev. 2006 Sep;58(3):488-520
references.pmid: 16968949
references.citation: Science. 2003 Feb 7;299(5608):896-9
references.pmid: 12574632
references.citation: J Biol Chem. 2007 Jan 26;282(4):2355-62
references.pmid: 17116659
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16507-12
references.pmid: 15545607
references.citation: Adv Physiol Educ. 2006 Dec;30(4):145-51
references.pmid: 17108241
references.citation: J Pharmacol Exp Ther. 2012 Jul;342(1):106-18
references.pmid: 22490378
references.citation: J Pharmacol Exp Ther. 2010 May;333(2):593-601
references.pmid: 20103585
references.citation: Am J Physiol Renal Physiol. 2012 Apr 1;302(7):F853-64
references.pmid: 22160772
references.citation: Endocrinology. 2007 Jul;148(7):3441-8
references.pmid: 17446185
references.citation: Nephron Physiol. 2007;105(1):p1-10
references.pmid: 17095876
references.citation: Am J Clin Nutr. 2011 Apr;93(4):884S-90
references.pmid: 21289221
references.citation: Cell. 1998 Mar 20;92(6):829-39
references.pmid: 9529258
references.citation: Transplantation. 2002 Feb 27;73(4):493-9
references.pmid: 11889418
references.citation: Kidney Int. 2004 Aug;66(2):514-7
references.pmid: 15253700
references.citation: Urology. 2012 Dec;80(6):1390.e1-6
references.pmid: 23010343
references.citation: EMBO Rep. 2009 Dec;10(12):1301-5
references.pmid: 19949411
references.citation: Trends Endocrinol Metab. 2012 Sep;23(9):459-66
references.pmid: 22817841
references.citation: Am J Pathol. 2006 May;168(5):1413-24
references.pmid: 16651609
references.citation: Mitochondrion. 2004 Sep;4(5-6):705-13
references.pmid: 16120426
references.citation: Free Radic Biol Med. 2013 Sep;62:90-101
references.pmid: 23200807
references.citation: Physiol Rev. 2008 Apr;88(2):611-38
references.pmid: 18391175
references.citation: J Clin Invest. 2013 Jan;123(1):469-78
references.pmid: 23257354
references.citation: J Biol Chem. 2013 Mar 8;288(10):6968-79
references.pmid: 23329826
references.citation: J Pharmacol Exp Ther. 2010 Feb;332(2):632-9
references.pmid: 19875674
references.citation: Am J Physiol Endocrinol Metab. 2011 Feb;300(2):E341-9
references.pmid: 21098736
references.citation: Endocr Rev. 2003 Feb;24(1):78-90
references.pmid: 12588810
references.citation: Physiol Rev. 2011 Apr;91(2):651-90
references.pmid: 21527734
references.citation: Mitochondrion. 2013 Mar;13(2):134-42
references.pmid: 23347985
references.citation: Cardiovasc Drugs Ther. 1993 Aug;7(4):655-60
references.pmid: 8241008
references.citation: Nat Rev Drug Discov. 2013 Jun;12(6):465-83
references.pmid: 23666487
references.citation: J Endocrinol Invest. 2011 Nov;34(10):738-41
references.pmid: 22234177
references.citation: Circ Res. 2012 Oct 12;111(9):1208-21
references.pmid: 23065344
references.citation: Neurology. 2012 Sep 25;79(13 Suppl 1):S44-51
references.pmid: 23008411
references.citation: Exp Neurobiol. 2013 Mar;22(1):11-7
references.pmid: 23585717