Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria.
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Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria. / Brähler, Sebastian; Ising, Christina; Hagmann, Henning; Rasmus, Melanie; Hoehne, Martin; Kurschat, Christine; Kisner, Tuelay; Goebel, Heike; Shankland, Stuart; Addicks, Klaus; Thaiss, Friedrich; Schermer, Bernhard; Pasparakis, Manolis; Benzing, Thomas; Brinkkoetter, Paul Thomas.
in: AM J PHYSIOL-RENAL, Jahrgang 303, Nr. 10, 10, 2012, S. 1473-1485.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria.
AU - Brähler, Sebastian
AU - Ising, Christina
AU - Hagmann, Henning
AU - Rasmus, Melanie
AU - Hoehne, Martin
AU - Kurschat, Christine
AU - Kisner, Tuelay
AU - Goebel, Heike
AU - Shankland, Stuart
AU - Addicks, Klaus
AU - Thaiss, Friedrich
AU - Schermer, Bernhard
AU - Pasparakis, Manolis
AU - Benzing, Thomas
AU - Brinkkoetter, Paul Thomas
PY - 2012
Y1 - 2012
N2 - Inflammation conveys the development of glomerular injury and is a major cause of progressive kidney disease. NF-?B 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-?B signaling in podocytes by specific ablation of the NF-?B essential modulator (NEMO, IKK?). 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-?B to the nucleus after stimulation with TNF? or IL-1 was sufficiently inhibited. Moreover, secretion of proinflammatory chemokines from podocytes after stimulation with TNF? 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-?B 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.
AB - Inflammation conveys the development of glomerular injury and is a major cause of progressive kidney disease. NF-?B 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-?B signaling in podocytes by specific ablation of the NF-?B essential modulator (NEMO, IKK?). 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-?B to the nucleus after stimulation with TNF? or IL-1 was sufficiently inhibited. Moreover, secretion of proinflammatory chemokines from podocytes after stimulation with TNF? 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-?B 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.
KW - Animals
KW - Humans
KW - Disease Models, Animal
KW - Mice
KW - Mice, Knockout
KW - HEK293 Cells
KW - RNA Interference
KW - NF-kappa B/metabolism
KW - Tumor Necrosis Factor-alpha/pharmacology
KW - Interleukin-1/pharmacology
KW - Signal Transduction/drug effects/physiology
KW - Glomerulonephritis/metabolism/pathology
KW - I-kappa B Kinase/genetics/metabolism
KW - Inflammation/metabolism/pathology
KW - Macrophages/metabolism/pathology
KW - Podocytes/drug effects/metabolism/pathology
KW - Proteinuria/metabolism/pathology
KW - T-Lymphocytes/metabolism/pathology
KW - Animals
KW - Humans
KW - Disease Models, Animal
KW - Mice
KW - Mice, Knockout
KW - HEK293 Cells
KW - RNA Interference
KW - NF-kappa B/metabolism
KW - Tumor Necrosis Factor-alpha/pharmacology
KW - Interleukin-1/pharmacology
KW - Signal Transduction/drug effects/physiology
KW - Glomerulonephritis/metabolism/pathology
KW - I-kappa B Kinase/genetics/metabolism
KW - Inflammation/metabolism/pathology
KW - Macrophages/metabolism/pathology
KW - Podocytes/drug effects/metabolism/pathology
KW - Proteinuria/metabolism/pathology
KW - T-Lymphocytes/metabolism/pathology
M3 - SCORING: Journal article
VL - 303
SP - 1473
EP - 1485
JO - AM J PHYSIOL-RENAL
JF - AM J PHYSIOL-RENAL
SN - 1931-857X
IS - 10
M1 - 10
ER -
