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KLF4 in Macrophages Attenuates TNFα-Mediated Kidney Injury and Fibrosis.

Publication ,  Journal Article
Wen, Y; Lu, X; Ren, J; Privratsky, JR; Yang, B; Rudemiller, NP; Zhang, J; Griffiths, R; Jain, MK; Nedospasov, SA; Liu, BC; Crowley, SD
Published in: J Am Soc Nephrol
October 2019

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.

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Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

October 2019

Volume

30

Issue

10

Start / End Page

1925 / 1938

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Tumor Necrosis Factor-alpha
  • Mice
  • Male
  • Macrophages
  • Kruppel-Like Transcription Factors
  • Kruppel-Like Factor 4
  • Kidney Diseases
  • Kidney
  • Fibrosis
 

Citation

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Wen, Y., Lu, X., Ren, J., Privratsky, J. R., Yang, B., Rudemiller, N. P., … Crowley, S. D. (2019). KLF4 in Macrophages Attenuates TNFα-Mediated Kidney Injury and Fibrosis. J Am Soc Nephrol, 30(10), 1925–1938. https://doi.org/10.1681/ASN.2019020111
Wen, Yi, Xiaohan Lu, Jiafa Ren, Jamie R. Privratsky, Bo Yang, Nathan P. Rudemiller, Jiandong Zhang, et al. “KLF4 in Macrophages Attenuates TNFα-Mediated Kidney Injury and Fibrosis.J Am Soc Nephrol 30, no. 10 (October 2019): 1925–38. https://doi.org/10.1681/ASN.2019020111.
Wen Y, Lu X, Ren J, Privratsky JR, Yang B, Rudemiller NP, et al. KLF4 in Macrophages Attenuates TNFα-Mediated Kidney Injury and Fibrosis. J Am Soc Nephrol. 2019 Oct;30(10):1925–38.
Wen, Yi, et al. “KLF4 in Macrophages Attenuates TNFα-Mediated Kidney Injury and Fibrosis.J Am Soc Nephrol, vol. 30, no. 10, Oct. 2019, pp. 1925–38. Pubmed, doi:10.1681/ASN.2019020111.
Wen Y, Lu X, Ren J, Privratsky JR, Yang B, Rudemiller NP, Zhang J, Griffiths R, Jain MK, Nedospasov SA, Liu BC, Crowley SD. KLF4 in Macrophages Attenuates TNFα-Mediated Kidney Injury and Fibrosis. J Am Soc Nephrol. 2019 Oct;30(10):1925–1938.

Published In

J Am Soc Nephrol

DOI

EISSN

1533-3450

Publication Date

October 2019

Volume

30

Issue

10

Start / End Page

1925 / 1938

Location

United States

Related Subject Headings

  • Urology & Nephrology
  • Tumor Necrosis Factor-alpha
  • Mice
  • Male
  • Macrophages
  • Kruppel-Like Transcription Factors
  • Kruppel-Like Factor 4
  • Kidney Diseases
  • Kidney
  • Fibrosis