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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.
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Research Article Nephrology

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

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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 1

KLF5 is involved in UUO-induced renal injury.

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KLF5 is involved in UUO-induced renal injury.
(A) Immunohistochemical st...
(A) Immunohistochemical staining of KLF5 (red) in mouse kidneys. Left and right panels show portions of the cortex and medulla, respectively. Nuclei and cell membranes were stained using DAPI (blue) and wheat germ agglutinin (green), respectively. Scale bars: 20 μm. (B) KLF5 expression was confined to AQP2-expressing collecting duct cells in papilla. KLF5 (red), AQP2 (green), and nuclei (blue) are shown. Scale bar: 20 μm. (C) Expression of KLF5 protein in the collecting duct. Collecting duct (CD) cells were isolated from kidneys by centrifugal separation. The remaining renal cells were non-CD cells. β-Tubulin served as a loading control. (D) UUO-induced upregulation of KLF5 in the collecting duct. KLF5 (brown) was detected by immunostaining of sections of medulla under basal conditions (control) and at the indicated times after UUO. Scale bars: 50 μm. (E–G) Masson’s trichrome (E and F) and H&E (G) staining of wild-type and Klf5+/– kidneys 14 days after UUO. C, cortex; M, medulla; P, papilla. Scale bars: 1 mm (E), 20 μm (F), 500 μm (G). (H) Apoptotic cell fractions in kidneys from wild-type and Klf5+/– mice at the indicated days after UUO. Apoptotic cells were analyzed by TUNEL staining, as shown in Supplemental Figure 3A. #P < 0.05 versus wild-type at the same time point. n = 6. (I) Fibrotic area stained with picrosirius red 14 days after UUO. *P < 0.05. n = 6. Representative sections are shown in Supplemental Figure 3C.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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