Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 121, Issue 9, Pages 3425-3441Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI57582
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Funding
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- National Institute of Biomedical Innovation
- Japan Science and Technology Institute
- Sumitomo Foundation
- Takeda Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Mitsubishi Pharma Research Foundation
- Grants-in-Aid for Scientific Research [22229006] Funding Source: KAKEN
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Renal tubulointerstitial damage is the final common pathway leading from chronic kidney disease to end-stage renal disease. Inflammation is clearly involved in tubulointerstitial injury, but it remains unclear how the inflammatory processes are initiated and regulated. Here, we have shown that in the mouse kidney, the transcription factor Kruppel-like factor-5 (KLF5) is mainly expressed in collecting duct epithelial cells and that Klf5 haploinsufficient mice (Klf5(+/-) mice) exhibit ameliorated renal injury in the unilateral ureteral obstruction (UUO) model of tubulointerstitial disease. Additionally, Klf5 haploinsufficiency reduced accumulation of CD11b(+)F4/80(lo) cells, which expressed proinflammatory cytokines and induced apoptosis among renal epithelial cells, phenotypes indicative of M1-type macrophages. By contrast, it increased accumulation of CD11b(+)F4/80(hi) macrophages, which expressed CD206 and CD301 and contributed to fibrosis, in part via TGF-beta production - phenotypes indicative of M2-type macrophages. Interestingly, KLF5, in concert with C/EBP alpha, was found to induce expression of the chemotactic proteins S100A8 and S100A9, which recruited inflammatory monocytes to the kidneys and promoted their activation into M1-type macrophages. Finally, assessing the effects of bone marrow-specific Klf5 haploinsufficiency or collecting duct- or myeloid cell-specific Klf5 deletion confirmed that collecting duct expression of Klf5 is essential for inflammatory responses to UUO. Taken together, our results demonstrate that the renal collecting duct plays a pivotal role in the initiation and progression of tubulointerstitial inflammation.
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