title: Inhibition of mitochondrial complex-1 restores the downregulation of aquaporins in obstructive nephropathy.
abstract: Obstructive kidney disease is a common complication in the clinic. Downregulation of aquaporins (AQPs) in obstructed kidneys has been thought as a key factor leading to the polyuria and impairment of urine-concentrating capability after the release of kidney obstruction. The present study was to investigate the role of mitochondrial complex-1 in modulating AQPs in obstructive nephropathy. Following 7-day unilateral ureteral obstruction (UUO), AQP1, AQP2, AQP3, and vasopressin 2 (V2) receptor were remarkably reduced as determined by qRT-PCR and/or Western blotting. Notably, inhibition of mitochondrial complex-1 by rotenone markedly reversed the downregulation of AQP1, AQP2, AQP3, and V2In contrast, AQP4 was not affected by kidney obstruction or rotenone treatment. In a separate study, rotenone also attenuated AQPs' downregulation after 48-h UUO. To study the potential mechanisms in mediating the rotenone effects on AQPs, we examined the regulation of the COX-2/microsomal prostaglandin E synthase (mPGES)-1/PGE2/EP pathway and found that COX-2, mPGES-1, and renal PGE2content were all significantly elevated in obstructive kidneys, which was not affected by rotenone treatment. For EP receptors, EP2and EP4but not EP1and EP3were upregulated in obstructive kidneys. Importantly, rotenone strikingly suppressed EP1and EP4but not EP2and EP3receptors. However, treatment of EP1antagonist SC-51322 could not affect AQPs' reduction in obstructed kidneys. Collectively, these findings suggested an important role of mitochondrial dysfunction in modulating AQPs and V2receptor in obstructive nephropathy possibly via prostaglandin-independent mechanisms.
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China; Department of Pharmacy, Xuzhou Medical University, Xuzhou, China; Nanjing Key Laboratory of Pediatric, Nanjing Children Hospital, Affiliated to Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China; Nanjing Key Laboratory of Pediatric, Nanjing Children Hospital, Affiliated to Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Xuzhou Medical University, Xuzhou, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China; Nanjing Key Laboratory of Pediatric, Nanjing Children Hospital, Affiliated to Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China; Nanjing Key Laboratory of Pediatric, Nanjing Children Hospital, Affiliated to Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, Xuzhou Medical University, Xuzhou, China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China; Nanjing Key Laboratory of Pediatric, Nanjing Children Hospital, Affiliated to Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Guixia
authors.initials: G
authors.lastname: Ding
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China; Nanjing Key Laboratory of Pediatric, Nanjing Children Hospital, Affiliated to Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical University, Nanjing, China; Nanjing Key Laboratory of Pediatric, Nanjing Children Hospital, Affiliated to Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China jiazj72@hotmail.com.cn.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D051379:Mice; D000071876:Prostaglandin-E Synthases / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000378:metabolism*
chemical_list: D020346:Aquaporins; D017483:Receptors, Vasopressin; D014475:Uncoupling Agents; D012402:Rotenone; D051546:Cyclooxygenase 2; D000071876:Prostaglandin-E Synthases; D042967:Electron Transport Complex I
keywords: cyclooxygenase-2; mitochondrial dysfunction; prostaglandin E2; water channels