Yi Wen1,2, Xiaohan Lu1,2, Jiafa Ren1,2, Jamie R Privratsky3, Bo Yang1,2, Nathan P Rudemiller1,2, Jiandong Zhang1,2, Robert Griffiths1,2, Mukesh K Jain4, Sergei A Nedospasov5, Bi Cheng Liu6, Steven D Crowley7,2. 1. Division of Nephrology. 2. Departments of Medicine and. 3. Anesthesiology, Durham VA and Duke University Medical Center, Durham, North Carolina. 4. Department of Medicine, Case Cardiovascular Research Institute, Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio. 5. Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, Lomonosov Moscow State University, Moscow, Russia; and. 6. Institute of Nephrology, Zhongda Hospital, Southeast University, Nanjing, China. 7. Division of Nephrology, steven.d.crowley@duke.edu.
Abstract
BACKGROUND: Polarized macrophage populations can orchestrate both inflammation of the kidney and tissue repair during CKD. Proinflammatory M1 macrophages initiate kidney injury, but mechanisms through which persistent M1-dependent kidney damage culminates in fibrosis require elucidation. Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor that suppresses inflammatory signals, is an essential regulator of macrophage polarization in adipose tissues, but the effect of myeloid KLF4 on CKD progression is unknown. METHODS: We used conditional mutant mice lacking KLF4 or TNFα (KLF4's downstream effector) selectively in myeloid cells to investigate macrophage KLF4's role in modulating CKD progression in two models of CKD that feature robust macrophage accumulation, nephrotoxic serum nephritis, and unilateral ureteral obstruction. RESULTS: In these murine CKD models, KLF4 deficiency in macrophages infiltrating the kidney augmented their M1 polarization and exacerbated glomerular matrix deposition and tubular epithelial damage. During the induced injury in these models, macrophage-specific KLF4 deletion also exacerbated kidney fibrosis, with increased levels of collagen 1 and α-smooth muscle actin in the injured kidney. CD11b+Ly6Chi myeloid cells isolated from injured kidneys expressed higher levels of TNFα mRNA versus wild-type controls. In turn, mice bearing macrophage-specific deletion of TNFα exhibited decreased glomerular and tubular damage and attenuated kidney fibrosis in the models. Moreover, treatment with the TNF receptor-1 inhibitor R-7050 during nephrotoxic serum nephritis reduced damage, fibrosis, and necroptosis in wild-type mice and mice with KLF4-deficient macrophages, and abrogated the differences between the two groups in these parameters. CONCLUSIONS: These data indicate that macrophage KLF4 ameliorates CKD by mitigating TNF-dependent injury and fibrosis.
BACKGROUND: Polarized macrophage populations can orchestrate both inflammation of the kidney and tissue repair during CKD. Proinflammatory M1 macrophages initiate kidney injury, but mechanisms through which persistent M1-dependent kidney damage culminates in fibrosis require elucidation. Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor that suppresses inflammatory signals, is an essential regulator of macrophage polarization in adipose tissues, but the effect of myeloid KLF4 on CKD progression is unknown. METHODS: We used conditional mutant mice lacking KLF4 or TNFα (KLF4's downstream effector) selectively in myeloid cells to investigate macrophage KLF4's role in modulating CKD progression in two models of CKD that feature robust macrophage accumulation, nephrotoxic serum nephritis, and unilateral ureteral obstruction. RESULTS: In these murine CKD models, KLF4 deficiency in macrophages infiltrating the kidney augmented their M1 polarization and exacerbated glomerular matrix deposition and tubular epithelial damage. During the induced injury in these models, macrophage-specific KLF4 deletion also exacerbated kidney fibrosis, with increased levels of collagen 1 and α-smooth muscle actin in the injured kidney. CD11b+Ly6Chi myeloid cells isolated from injured kidneys expressed higher levels of TNFα mRNA versus wild-type controls. In turn, mice bearing macrophage-specific deletion of TNFα exhibited decreased glomerular and tubular damage and attenuated kidney fibrosis in the models. Moreover, treatment with the TNF receptor-1 inhibitor R-7050 during nephrotoxic serum nephritis reduced damage, fibrosis, and necroptosis in wild-type mice and mice with KLF4-deficient macrophages, and abrogated the differences between the two groups in these parameters. CONCLUSIONS: These data indicate that macrophage KLF4 ameliorates CKD by mitigating TNF-dependent injury and fibrosis.
Authors: Andreas Linkermann; Jan-Ole Heller; Agnes Prókai; Joel M Weinberg; Federica De Zen; Nina Himmerkus; Attila J Szabó; Jan H Bräsen; Ulrich Kunzendorf; Stefan Krautwald Journal: J Am Soc Nephrol Date: 2013-07-05 Impact factor: 10.121
Authors: James A Rickard; Joanne A O'Donnell; Joseph M Evans; Najoua Lalaoui; Ashleigh R Poh; TeWhiti Rogers; James E Vince; Kate E Lawlor; Robert L Ninnis; Holly Anderton; Cathrine Hall; Sukhdeep K Spall; Toby J Phesse; Helen E Abud; Louise H Cengia; Jason Corbin; Sandra Mifsud; Ladina Di Rago; Donald Metcalf; Matthias Ernst; Grant Dewson; Andrew W Roberts; Warren S Alexander; James M Murphy; Paul G Ekert; Seth L Masters; David L Vaux; Ben A Croker; Motti Gerlic; John Silke Journal: Cell Date: 2014-05-08 Impact factor: 41.582
Authors: A Lau; S Wang; J Jiang; A Haig; A Pavlosky; A Linkermann; Z-X Zhang; A M Jevnikar Journal: Am J Transplant Date: 2013-09-18 Impact factor: 8.086
Authors: Claudia Günther; Eva Martini; Nadine Wittkopf; Kerstin Amann; Benno Weigmann; Helmut Neumann; Maximilian J Waldner; Stephen M Hedrick; Stefan Tenzer; Markus F Neurath; Christoph Becker Journal: Nature Date: 2011-09-14 Impact factor: 49.962
Authors: Shrikant R Mulay; Jyaysi Desai; Santhosh V Kumar; Jonathan N Eberhard; Dana Thomasova; Simone Romoli; Melissa Grigorescu; Onkar P Kulkarni; Bastian Popper; Volker Vielhauer; Gabriele Zuchtriegel; Christoph Reichel; Jan Hinrich Bräsen; Paola Romagnani; Rostyslav Bilyy; Luis E Munoz; Martin Herrmann; Helen Liapis; Stefan Krautwald; Andreas Linkermann; Hans-Joachim Anders Journal: Nat Commun Date: 2016-01-28 Impact factor: 14.919
Authors: Yi Wen; Nathan P Rudemiller; Jiandong Zhang; Taylor Robinette; Xiaohan Lu; Jiafa Ren; Jamie R Privratsky; Sergei A Nedospasov; Steven D Crowley Journal: Am J Physiol Renal Physiol Date: 2019-11-18