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.
View: Text | PDF
Research Article Nephrology

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

×

Figure 5

EPO-producing fibroblasts also transform into myofibroblasts, hindering EPO production.

Options: View larger image (or click on image) Download as PowerPoint
EPO-producing fibroblasts also transform into myofibroblasts, hindering ...
(A) In situ hybridization demonstrated that Epo mRNA detected in the control kidney was almost undetectable in the operated kidneys at day 14 of UUO. Hybridization with a sense probe did not elicit any signals in the control kidney. AS, antisense; S, sense. (B) Expression of Epo mRNA in the operated kidney decreased significantly, as early as 12 hours after ligation of the ureter (n = 5/group, except for the group sacrificed at day 5 [d5], in which n = 4). NT, nontreated. (C) The suppression of Epo mRNA in the operated kidneys was reversed after the induction of anemia. Each dot represents renal expression of Epo in an individual mouse (n = 5 in UUO group; n = 9 in UUO plus anemia group). (D) Undetectable GFP+ cells in the operated kidneys of Epo-GFP mice became detectable after the induction of anemia and colocalized with α-SMA. (E) The expression of Epo in cultured myofibroblasts was augmented by the administration of low-dose dexamethasone, neurotrophins, and HGF. Vehicle used was 0.05% ethanol for the control of dexamethasone. Data are representative of results of 5 independent experiments. (F) Expression of Epo mRNA in UUO kidneys was significantly restored, whereas the expression of Col1a1 and fibronectin (Fn1) mRNA was decreased by tamoxifen treatment (n = 5). Vehicle used was 100 μl of 10% ethanol in sunflower oil. Expression of Epo, Col1a1, and Fn1 was normalized to that of Gapdh and expressed relative to that in (B and E) the nontreated group or (F) vehicle-treated group. Scale bars: 10 μm.