Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)3981-3990
Number of pages10
JournalJournal of Clinical Investigation
Volume121
Issue number10
DOIs
Publication statusPublished - 2011 Oct 3

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Anemia
Fibrosis
Fibroblasts
Kidney
Erythropoietin
Myofibroblasts
Chronic Renal Insufficiency
Myelin P0 Protein
Selective Estrogen Receptor Modulators
Epithelial-Mesenchymal Transition
Erythropoiesis
Nerve Growth Factors
Kidney Diseases
Neuroprotective Agents
Tamoxifen
Dexamethasone
Epithelial Cells
Hormones

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Asada, N., Takase, M., Nakamura, J., Oguchi, A., Asada, M., Suzuki, N., ... Yanagita, M. (2011). Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. Journal of Clinical Investigation, 121(10), 3981-3990. https://doi.org/10.1172/JCI57301

Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. / Asada, Nariaki; Takase, Masayuki; Nakamura, Jin; Oguchi, Akiko; Asada, Misako; Suzuki, Norio; Yamamura, Ken Ichi; Nagoshi, Narihito; Shibata, Shinsuke; Rao, Tata Nageswara; Fehling, Hans Joerg; Fukatsu, Atsushi; Minegishi, Naoko; Kita, Toru; Kimura, Takeshi; Okano, Hideyuki; Yamamoto, Masayuki; Yanagita, Motoko.

In: Journal of Clinical Investigation, Vol. 121, No. 10, 03.10.2011, p. 3981-3990.

Research output: Contribution to journalArticle

Asada, N, Takase, M, Nakamura, J, Oguchi, A, Asada, M, Suzuki, N, Yamamura, KI, Nagoshi, N, Shibata, S, Rao, TN, Fehling, HJ, Fukatsu, A, Minegishi, N, Kita, T, Kimura, T, Okano, H, Yamamoto, M & Yanagita, M 2011, 'Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice', Journal of Clinical Investigation, vol. 121, no. 10, pp. 3981-3990. https://doi.org/10.1172/JCI57301
Asada, Nariaki ; Takase, Masayuki ; Nakamura, Jin ; Oguchi, Akiko ; Asada, Misako ; Suzuki, Norio ; Yamamura, Ken Ichi ; Nagoshi, Narihito ; Shibata, Shinsuke ; Rao, Tata Nageswara ; Fehling, Hans Joerg ; Fukatsu, Atsushi ; Minegishi, Naoko ; Kita, Toru ; Kimura, Takeshi ; Okano, Hideyuki ; Yamamoto, Masayuki ; Yanagita, Motoko. / Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 10. pp. 3981-3990.
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