KLF4 in Macrophages Attenuates TNFα-Mediated Kidney Injury and Fibrosis

<jats:sec> <jats:title>Significance Statement</jats:title> <jats:p>Proinflammatory M1 macrophages initiate kidney injury, but mechanisms through which persistent M1-dependent kidney damage culminates in fibrosis of the kidney require elucidation. In murine CKD models featuring robust macrophage accumulation, the authors found that macrophage-specific deficiency of Krüppel-like factor 4 (KLF4, a zinc-finger transcription factor that suppresses inflammation) augmented the M1 polarization and expression of TNF<jats:italic toggle="yes">α</jats:italic> (KLF4’s downstream effector) in macrophages infiltrating the kidney, as well as exacerbated glomerular matrix deposition, tubular damage, and interstitial fibrosis. Mice with macrophage-specific TNF deletion exhibited decreased kidney damage and fibrosis. TNF receptor-1 inhibition in wild-type mice and mice with macrophage-specific KLF4 deficiency reduced susceptibility to kidney damage, fibrosis, and necroptosis, and abrogated differences in these parameters between experimental groups. These findings indicate that macrophage KLF4 ameliorates CKD by mitigating TNF-dependent injury and fibrosis.</jats:p> </jats:sec> <jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>We used conditional mutant mice lacking KLF4 or TNF<jats:italic toggle="yes">α</jats:italic> (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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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 <jats:italic toggle="yes">α</jats:italic>-smooth muscle actin in the injured kidney. CD11b<jats:sup>+</jats:sup>Ly6C<jats:sup>hi</jats:sup> myeloid cells isolated from injured kidneys expressed higher levels of TNF<jats:italic toggle="yes">α</jats:italic> mRNA versus wild-type controls. In turn, mice bearing macrophage-specific deletion of TNF<jats:italic toggle="yes">α</jats:italic> 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These data indicate that macrophage KLF4 ameliorates CKD by mitigating TNF-dependent injury and fibrosis.</jats:p> </jats:sec>