Abstract: FR-PO1063
KLF4 on Macrophages Attenuates TNF-α Mediated Kidney Inflammation and Fibrosis in Autoimmune Nephritis
Session Information
- Glomerular Diseases: Immunology and Inflammation - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Wen, Yi, Duke University Medical Center, Durham, North Carolina, United States
- Privratsky, Jamie, Duke University Medical Center, Durham, North Carolina, United States
- Lu, Xiaohan, Duke University Medical Center, Durham, North Carolina, United States
- Ren, Jiafa, Duke University Medical Center, Durham, North Carolina, United States
- Liu, Bi-Cheng, Zhong Da Hospital, Southeast University Medical School, Nanjing, JIangSu, China
- Crowley, Steven D., Duke University Medical Center, Durham, North Carolina, United States
Background
The Kruppel-like factor (KLF) family of transcriptional regulators play complex roles in the pathogenesis of kidney disease. We recently found that activating type 1 angiotensin receptors in macrophages upregulates KLF4 and paradoxically limits renal fibrosis. As KLF4 attenuates NF-kB-dependent vascular injury, we directly investigated the role of macrophage KLF4 in renal inflammation and fibrosis using the murine nephrotoxic serum nephritis (NTS) model. As KLF4 suppressed TNF-α in intra-renal macrophages in our studies, we additionally probed the contribution of macrophage TNF-α to NTS progression.
Methods
Mice with floxed alleles for the genes encoding KLF4 or TNF-α were bred with LysM-Cre mice to yield KLF4 or TNF “MKO” mice with macrophage-specific deletion of KLF4 or TNF-α, respectively. NTS was induced in KLF4 MKO, TNF MKO, and wild-type (WT) littermate control mice by IV injections of sheep IgG followed 5 days later by sheep anti-mouse GBM serum.
Results
At day 14 NTS, KLF4 MKO mice compared to WTs had augmented glomerular matrix deposition (44.4 ± 3.3 vs 33.7 ± 2.5%; P = 0.04), urinary albumin/Cr ratios (7.7 ± 0.8 vs 5.3 ± 0.6 mg/mg; P = 0.05), and renal NGAL mRNA (1.3 ± 0.1 vs 1.0 ± 0.2 au; P = 0.03). KLF4 MKO kidneys also showed increased mRNA levels for collagen 1 (1.9 ± 0.2 vs 1.0 ± 0.3 au; P = 0.01), fibronectin (1.7 ± 0.2 vs 1.0 ± 0.2 au; P = 0.03), and the fibrosis mediators TGF-β (1.4 ± 0.1 vs 1.0 ± 0.2 au; P = 0.03) and PAI-1 (1.4 ± 0.1 vs 1.0 ± 0.2 au; P = 0.03). CD11b+ Ly6Chi inflammatory macrophages isolated directly from NTS kidneys of KLF4 MKO animals had 50% higher TNF-α expression than WTs (1.5 ± 0.1 vs 1.0 ± 0.1 au; P = 0.04). To explore whether macrophage KLF4 protects the kidney by suppressing TNF-α, we repeated our NTS studies in TNF MKO mice and WT controls. At day 14 of NTS, TNF MKOs compared to WTs had reduced glomerular matrix deposition (33.2 ± 0.6% vs 43.8 ± 1.6%; P ＜ 0.01), urine albumin/Cr ratios (3.6 ± 0.4 vs 4.7 ± 0.3 mg/mg; P = 0.04), and mRNA levels for NGAL (0.5 ± 0.1 vs 1.0 ± 0.2 au; P = 0.02), collagen 1(0.5 ± 0.2 vs 1.0 ± 0.2 au; P = 0.04), aSMA (0.3 ± 0.1 vs 1.0 ± 0.2 au; P ＜ 0.01), and PAI-1 (0.6 ± 0.1 vs 1.0 ± 0.1 au; P ＜ 0.01).
Conclusion
KLF4 activation on macrophages mitigates renal injury and fibrosis during NTS by inhibiting production of macrophage-derived TNF-α.
Funding
- NIDDK Support