title: Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria.
abstract: Inflammation conveys the development of glomerular injury and is a major cause of progressive kidney disease. NF-κB signaling is among the most important regulators of proinflammatory signaling. Its role in podocytes, the epithelial cells at the kidney filtration barrier, is poorly understood. Here, we inhibited NF-κB signaling in podocytes by specific ablation of the NF-κB essential modulator (NEMO, IKKγ). Podocyte-specific NEMO-deficient mice (NEMO(pko)) were viable and did not show proteinuria or overt changes in kidney morphology. After induction of glomerulonephritis, both NEMO(pko) and control mice developed significant proteinuria. However, NEMO(pko) mice recovered much faster, showing rapid remission of proteinuria and restoration of podocyte morphology. Interestingly, quantification of infiltrating macrophages, T-lymphocytes, and granulocytes at day 7 revealed no significant difference between wild-type and NEMO(pko). To further investigate the underlying mechanisms, we created a stable NEMO knockdown mouse podocyte cell line. Again, no overt changes in morphology were observed. Translocation of NF-κB to the nucleus after stimulation with TNFα or IL-1 was sufficiently inhibited. Moreover, secretion of proinflammatory chemokines from podocytes after stimulation with TNFα or IL-1 was significantly reduced in NEMO-deficient podocytes and in glomerular samples obtained at day 7 after induction of nephrotoxic nephritis. Collectively, these results show that proinflammatory activity of NF-κB in podocytes aggravates proteinuria in experimental glomerulonephritis in mice. Based on these data, it may be speculated that immunosuppressive drugs may not only target professional immune cells but also podocytes directly to convey their beneficial effects in various types of glomerulonephritis.
authors.affiliation: Univ. of Cologne, Dept. II of Internal Medicine, Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brähler
authors.forename: Christina
authors.initials: C
authors.lastname: Ising
authors.forename: Henning
authors.initials: H
authors.lastname: Hagmann
authors.forename: Melanie
authors.initials: M
authors.lastname: Rasmus
authors.forename: Martin
authors.initials: M
authors.lastname: Hoehne
authors.forename: Christine
authors.initials: C
authors.lastname: Kurschat
authors.forename: Tuelay
authors.initials: T
authors.lastname: Kisner
authors.forename: Heike
authors.initials: H
authors.lastname: Goebel
authors.forename: Stuart
authors.initials: S
authors.lastname: Shankland
authors.forename: Klaus
authors.initials: K
authors.lastname: Addicks
authors.forename: Friedrich
authors.initials: F
authors.lastname: Thaiss
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Paul Thomas
authors.initials: PT
authors.lastname: Brinkkoetter
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007375:Interleukin-1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase