Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice
Katsuhito Fujiu, Ichiro Manabe, Ryozo Nagai
Katsuhito Fujiu, Ichiro Manabe, Ryozo Nagai
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Research Article Nephrology

Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice

Abstract

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 Krüppel-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+F4/80lo 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+F4/80hi macrophages, which expressed CD206 and CD301 and contributed to fibrosis, in part via TGF-β production — phenotypes indicative of M2-type macrophages. Interestingly, KLF5, in concert with C/EBPα, 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.

Authors

Katsuhito Fujiu, Ichiro Manabe, Ryozo Nagai

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Figure 10

UUO alters KLF5 binding targets in vivo.

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UUO alters KLF5 binding targets in vivo. (A and B) ChIP assays for KLF5 ...
(A and B) ChIP assays for KLF5 (A) and C/EBPα (B) binding to their target promoters in IMCD cells isolated from kidneys subjected to either UUO or sham operation. One percent of the input chromatin from IMCD cells isolated from the sham-operated kidneys was used as a positive control (Input). Samples prepared from UUO kidneys and immunoprecipitated with nonimmune IgG were used as a negative control. ChIP assays using a nontarget region (Pdgfa 3ιUTR) as a negative control are shown in Supplemental Figure 15A. (C and D) In vivo re-ChIP analysis of the simultaneous binding of KLF5 and C/EBPα to the S100a8 (C) and S100a9 (D) promoters. Chromatin samples prepared from renal papillary cells of control (Ctrl) and 12- and 24-hour UUO kidneys were subjected to immunoprecipitation using KLF5 or C/EBPα antibody (1° ChIP). The immunoprecipitates were then pulled down further using C/EBPα or KLF5 antibody, respectively (2° ChIP). ChIP assays of a nontarget region (Pdgfa 3′UTR) are shown in Supplemental Figure 15B.