Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice
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慢性腎臓病の2大合併症である腎臓の線維化と腎性貧血のメカニズムの解明. 京都大学プレスリリース. 2011-09-13.In chronic kidney disease, fibroblast dysfunction causes renal fibrosis and renal anemia. Renal fibrosis ismediated by the accumulation of myofibroblasts, whereas renal anemia is mediated by the reduced productionof fibroblast-derived erythropoietin, a hormone that stimulates erythropoiesis. Despite their importance inchronic kidney disease, the origin and regulatory mechanism of fibroblasts remain unclear. Here, we have demonstratedthat the majority of erythropoietin-producing fibroblasts in the healthy kidney originate from myelinprotein zero–Cre (P0-Cre) lineage-labeled extrarenal cells, which enter the embryonic kidney at E13.5. In thediseased kidney, P0-Cre lineage-labeled fibroblasts, but not fibroblasts derived from injured tubular epithelialcells through epithelial-mesenchymal transition, transdifferentiated into myofibroblasts and predominantlycontributed to fibrosis, with concomitant loss of erythropoietin production. We further demonstrated thatattenuated erythropoietin production in transdifferentiated myofibroblasts was restored by the administrationof neuroprotective agents, such as dexamethasone and neurotrophins. Moreover, the in vivo administration oftamoxifen, a selective estrogen receptor modulator, restored attenuated erythropoietin production as well asfibrosis 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.
- 2011-09-12
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