title: Renal nerves drive interstitial fibrogenesis in obstructive nephropathy.
abstract: The signals that drive fibrogenesis after an initiating insult to the kidney are incompletely understood. Here, we report that renal nerve stimulation after ureteral obstruction is the primary profibrotic signal and that renal denervation prevents both fibrogenesis and the inflammatory cascade. Local infusion of neural factors, norepinephrine, and calcitonin gene-related peptide (CGRP) in denervated kidneys mimicked the fibrotic response observed in innervated obstructed kidneys. Norepinephrine and CGRP act through the α(2)-adrenergic receptor and CGRP receptor, respectively, because blocking these receptors prevented fibrosis, the inflammatory response, and tubular cell death. In tubular epithelial cells, both norepinephrine and CGRP induced apoptosis and the release of profibrotic factors capable of stimulating the differentiation of fibroblasts to myofibroblasts. In conclusion, these data suggest that nerve-derived signaling molecules may drive renal fibrosis and that their suppression may be a therapeutic approach to fibrosis prevention.
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5850, USA.
authors.forename: Jinu
authors.initials: J
authors.lastname: Kim
authors.forename: Babu J
authors.initials: BJ
authors.lastname: Padanilam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D003714:Denervation / Q000379:methods; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000294:innervation* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D009336:Necrosis; D009393:Nephritis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009475:Neurons, Afferent / Q000378:metabolism; D009476:Neurons, Efferent / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018341:Receptors, Adrenergic, alpha-2; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D020169:Caspases; D015740:Calcitonin Gene-Related Peptide; D009638:Norepinephrine