title: Renal denervation prevents long-term sequelae of ischemic renal injury.
abstract: Signals that drive interstitial fibrogenesis after renal ischemia reperfusion injury remain undefined. Sympathetic activation manifests even in the early clinical stages of chronic kidney disease and is directly related to disease severity. A role for renal nerves in renal interstitial fibrogenesis in the setting of ischemia reperfusion injury has not been studied. In male 129S1/SvImJ mice, ischemia reperfusion injury induced tubulointerstitial fibrosis as indicated by collagen deposition and profibrotic protein expression 4 to 16 days after the injury. Leukocyte influx, proinflammatory protein expression, oxidative stress, apoptosis, and cell cycle arrest at G2/M phase were enhanced after ischemia reperfusion injury. Renal denervation at the time of injury or up to 1 day post injury improved histology, decreased proinflammatory/profibrotic responses and apoptosis, and prevented G2/M cell cycle arrest in the kidney. Treatment with afferent nerve-derived calcitonin gene-related peptide (CGRP) or efferent nerve-derived norepinephrine in denervated and ischemia reperfusion injury-induced kidneys mimicked innervation, restored inflammation and fibrosis, induced G2/M arrest, and enhanced TGF-β1 activation. Blocking norepinephrine or CGRP function using respective receptor blockers prevented these effects. Consistent with the in vivo study, treatment with either norepinephrine or CGRP induced G2/M cell cycle arrest in HK-2 proximal tubule cells, whereas antagonists against their respective receptors prevented G2/M arrest. Thus, renal nerve stimulation is a primary mechanism and renal nerve-derived factors drive epithelial cell cycle arrest and the inflammatory cascade causing interstitial fibrogenesis after ischemia reperfusion injury.
authors.affiliation: 1] Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, USA [2] Department of Anatomy, Jeju National University School of Medicine, Jeju, Republic of Korea.
authors.forename: Jinu
authors.initials: J
authors.lastname: Kim
authors.affiliation: 1] Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, USA [2] Department of Internal Medicine, Section of Nephrology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Babu J
authors.initials: BJ
authors.lastname: Padanilam
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D003714:Denervation; D004195:Disease Models, Animal; D005355:Fibrosis; D059565:G2 Phase Cell Cycle Checkpoints; D007668:Kidney / Q000098:blood supply* / Q000293:injuries / Q000294:innervation*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D053773:Transforming Growth Factor beta1; D015740:Calcitonin Gene-Related Peptide; D009638:Norepinephrine