Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice
Katsuhito Fujiu, … , Ichiro Manabe, Ryozo Nagai
Katsuhito Fujiu, … , Ichiro Manabe, Ryozo Nagai
Published August 8, 2011
Citation Information: J Clin Invest. 2011;121(9):3425-3441. https://doi.org/10.1172/JCI57582.
View: Text | PDF
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

×

Figure 8

S100A8 and S100A9 induce M1-type activation and accumulation of CD11b+F4/80lo cells.

Options: View larger image (or click on image) Download as PowerPoint
S100A8 and S100A9 induce M1-type activation and accumulation of CD11b+F4...
(A) Effects of S100A8/A9 on M1 or M2 activation of BMDMs. Unstimulated BMDMs were treated with IFN-γ plus LPS, S100A8 plus S100A9 (3 and 10 μg/ml of each), or IL-4 for 24 hours, and expression of M1 and M2 markers was analyzed. Expression levels were normalized to those of 18s rRNA and then further normalized to the levels in BMDMs without stimulation, except Arg1. *P < 0.05 versus untreated control. n = 3. (B) Effect of renal injection of recombinant S100A8 and S100A9 on macrophage accumulation. A solution of recombinant S100A8 and S100A9 (S100; 25 μg of each protein) was injected directly into the right kidney. The same amount of vehicle PBS, PBS containing LPS at a concentration (9.2 pg/ml) matched to that in the S100A8/A9 solution (LPS), or PBS whose osmolarity was matched to that of the S100 solution using glucose (iso-Glc) was injected into kidneys as control. CD11b+F4/80lo and CD11b+F4/80hi fractions among total live cells were determined by flow cytometry. n = 3. *P < 0.05 versus kidneys 12 hours after PBS injection. (C) CD11b+Ly-6C+EGFP+ BM cells (1 × 106 cells/mouse) were prepared from CAG-EGFP mice and adoptively transferred into wild-type mice prior to a single injection of PBS or S100A8 plus S100A9 (25 μg of each) into kidneys. Transferred EGFP+ cells recruited to kidneys were analyzed by flow cytometry. Cells in R1 (CD11b+F4/80lo) were further analyzed for expression of Ly-6C and CD301.