title: Inhibition of Mitochondrial Complex-1 Prevents the Downregulation of NKCC2 and ENaCα in Obstructive Kidney Disease.
abstract: Ureteral obstruction with subsequent hydronephrosis is a common clinical complication. Downregulation of renal sodium transporters in obstructed kidneys could contribute to impaired urinary concentrating capability and salt waste following the release of a ureteral obstruction. The current study was undertaken to investigate the role of mitochondrial complex-1 inhibition in modulating sodium transporters in obstructive kidney disease. Following unilateral ureteral obstruction (UUO) for 7 days, a global reduction of sodium transporters, including NHE3, α-Na-K-ATPase, NCC, NKCC2, p-NKCC2, ENaCα, and ENaCγ, was observed, as determined via qRT-PCR and/or Western blotting. Interestingly, inhibition of mitochondrial complex-1 by rotenone markedly reversed the downregulation of NKCC2, p-NKCC2, and ENaCα. In contrast, other sodium transporters were not affected by rotenone. To study the potential mechanisms involved in mediating the effects of rotenone on sodium transporters, we examined a number of known sodium modulators, including PGE2, ET1, Ang II, natriuretic peptides (ANP, BNP, and CNP), and nitric oxide synthases (iNOS, nNOS, and eNOS). Importantly, among these modulators, only BNP and iNOS were significantly reduced by rotenone treatment. Collectively, these findings demonstrated a substantial role of mitochondrial dysfunction in mediating the downregulation of NKCC2 and ENaCα in obstructive kidney disease, possibly via iNOS-derived nitric oxide and BNP.
authors.affiliation: 1] Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China [2] Institute of Pediatrics, Nanjing Medical University, Nanjing, China [3] Nanjing Key Laboratory of Pediatrics, Nanjing Children Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China [2] Institute of Pediatrics, Nanjing Medical University, Nanjing, China [3] Nanjing Key Laboratory of Pediatrics, Nanjing Children Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 1] Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China [2] Institute of Pediatrics, Nanjing Medical University, Nanjing, China [3] Nanjing Key Laboratory of Pediatrics, Nanjing Children Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China.
authors.forename: Guixia
authors.initials: G
authors.lastname: Ding
authors.affiliation: 1] Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China [2] Institute of Pediatrics, Nanjing Medical University, Nanjing, China [3] Nanjing Key Laboratory of Pediatrics, Nanjing Children Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China.
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
authors.affiliation: 1] Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China [2] Institute of Pediatrics, Nanjing Medical University, Nanjing, China [3] Nanjing Key Laboratory of Pediatrics, Nanjing Children Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
authors.affiliation: 1] Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China [2] Institute of Pediatrics, Nanjing Medical University, Nanjing, China [3] Nanjing Key Laboratory of Pediatrics, Nanjing Children Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D015232:Dinoprostone / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology*; D015398:Signal Transduction; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D064486:Solute Carrier Family 12, Member 3 / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D053503:Epithelial Sodium Channels; C507053:Scnn1g protein, mouse; C578715:Slc12a1 protein, mouse; C578875:Slc12a3 protein, mouse; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D012402:Rotenone; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D042967:Electron Transport Complex I; D000254:Sodium-Potassium-Exchanging ATPase; D015232:Dinoprostone