Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice
Nariaki Asada, … , Masayuki Yamamoto, Motoko Yanagita
Nariaki Asada, … , Masayuki Yamamoto, Motoko Yanagita
Published September 12, 2011
Citation Information: J Clin Invest. 2011;121(10):3981-3990. https://doi.org/10.1172/JCI57301.
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Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice

Abstract

In chronic kidney disease, fibroblast dysfunction causes renal fibrosis and renal anemia. Renal fibrosis is mediated by the accumulation of myofibroblasts, whereas renal anemia is mediated by the reduced production of fibroblast-derived erythropoietin, a hormone that stimulates erythropoiesis. Despite their importance in chronic kidney disease, the origin and regulatory mechanism of fibroblasts remain unclear. Here, we have demonstrated that the majority of erythropoietin-producing fibroblasts in the healthy kidney originate from myelin protein zero–Cre (P0-Cre) lineage-labeled extrarenal cells, which enter the embryonic kidney at E13.5. In the diseased kidney, P0-Cre lineage-labeled fibroblasts, but not fibroblasts derived from injured tubular epithelial cells through epithelial-mesenchymal transition, transdifferentiated into myofibroblasts and predominantly contributed to fibrosis, with concomitant loss of erythropoietin production. We further demonstrated that attenuated erythropoietin production in transdifferentiated myofibroblasts was restored by the administration of neuroprotective agents, such as dexamethasone and neurotrophins. Moreover, the in vivo administration of tamoxifen, a selective estrogen receptor modulator, restored attenuated erythropoietin production as well as fibrosis in a mouse model of kidney fibrosis. These findings reveal the pathophysiological roles of P0-Cre lineage-labeled fibroblasts in the kidney and clarify the link between renal fibrosis and renal anemia.

Authors

Nariaki Asada, Masayuki Takase, Jin Nakamura, Akiko Oguchi, Misako Asada, Norio Suzuki, Ken-ichi Yamamura, Narihito Nagoshi, Shinsuke Shibata, Tata Nageswara Rao, Hans Joerg Fehling, Atsushi Fukatsu, Naoko Minegishi, Toru Kita, Takeshi Kimura, Hideyuki Okano, Masayuki Yamamoto, Motoko Yanagita

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Figure 1

Most of the fibroblasts in the kidney arise from P0-Cre–expressing precursors.

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Most of the fibroblasts in the kidney arise from P0-Cre–expressing precu...
(A) Schematic drawing of the kidney, showing the localization of P0-Cre fate-mapped cells in the cortex and outer medulla. (B and C) ECFP+ cells were detected in the interstitium of the kidneys of P0-Cre/R26ECFP mice. A higher-magnification view is shown in C. (D–F) LacZ staining of P0-Cre/R26R kidney. (D and E) Note the similar distribution of LacZ+ cells in P0-Cre/R26R kidneys with ECFP+ cells in P0-Cre/R26ECFP mice. A higher-magnification view is shown in E. (F) No LacZ+ cells were observed in the kidneys of R26R mice without the P0-Cre allele. (G–I) Double immunostaining of ECFP+ cells in the P0-Cre/R26ECFP kidney. (G) Most, if not all, of the ECFP+ cells were negative for PECAM. (H and I) ECFP+ cells (H) in the kidney were positive for PDGFR-β, the fibroblast marker, whereas ECFP+ cells (I) in the cortex were also positive for CD73/5′NT, the marker for cortical fibroblasts. (J) Graph illustrating the proportion of PDGFR-β+ interstitial cells in the cortex and outer medulla coexpressing ECFP (% ECFP/PDGFR-β cells) and the proportion of ECFP+ interstitial cells coexpressing PDGFR-β (% PDGFR-β/ECFP cells). (K) In neonatal kidneys of P0-Cre/floxed-EGFP mice most of the EGFP+ cells were also positive for p75, a neural crest marker. Scale bars: 10 μm (B–I); 100 μm (K).