Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin

Kobayashi, Hanako; Liu, Qingdu; Binns, Thomas C; Urrutia, Andrés; Davidoff, Olena; Kapitsinou, Pinelopi P.; Pfaff, Andrew S.; Olauson, Hannes; Wernerson, Annika; Fogo, Agnes B.; Fong, Guo Hua; Gross, Kenneth W.; Haase, Volker H.

doi:10.1172/jci83551

Cited by 93 publications

(123 citation statements)

References 55 publications

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“…The damaged REP cells in this model exhibit significant plasticity in terms of EPO production (15), suggesting that epigenetic silencing of the Epo gene underlies gene repression in MF-REP cells in CKD. Recently, FOXD1-positive renal fibroblasts were determined to include REP cells, and hypermethylated status was detected in the cells under UUO conditions in the Ϫ8kHRE region, as well as the Epo gene coding locus (42)(43)(44). Consistent with these observations, we demonstrate here that the CURE region containing the Ϫ8kHRE is necessary for renal Epo gene regulation.…”

Section: Discussionsupporting

confidence: 88%

Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements

Hirano

Suzuki

Yamazaki

et al. 2017

Molecular and Cellular Biology

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The erythropoietin (Epo) gene is under tissue-specific inducible regulation. Because the kidney is the primary EPO-producing tissue in adults, impaired EPO production in chronic kidney disorders results in serious renal anemia. The Epo gene contains a liver-specific enhancer in the 3= region, but the kidney-specific enhancer for gene expression in renal EPO-producing (REP) cells remains elusive. Here, we examined a conserved upstream element for renal Epo regulation (CURE) region that spans 17.4 kb to 3.6 kb upstream of the Epo gene and harbors several phylogenetically conserved elements. We prepared various Epo gene-reporter constructs utilizing a bacterial artificial chromosome and generated a number of transgenic-mouse lines. We observed that deletion of the CURE region (␦CURE) abrogated Epo gene expression in REP cells. Although transgenic expression of the ␦CURE construct rescued Epo-deficient mice from embryonic lethality, the rescued mice had severe EPOdependent anemia. These mouse lines serve as an elaborate model for the search for erythroid stimulatory activity and are referred to as AnRED (anemic model with renal EPO deficiency) mice. We also dissected the CURE region by exploiting a minigene harboring four phylogenetically conserved elements in reporter transgenicmouse analyses. Our analyses revealed that Epo gene regulation in REP cells is a complex process that utilizes multiple regulatory influences.

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Section: Discussionsupporting

confidence: 88%

Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements

Hirano

Suzuki

Yamazaki

et al. 2017

Molecular and Cellular Biology

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“…The primary source of resident cortical renal fibroblasts, mesangial cells, pericytes, and vascular smooth muscle cells in the kidney are from Forkhead Box D1 (Foxd1) expressing stromal cells in the metanephric mesenchyme during kidney development 24 . Foxd1 is expressed in the stromal cells during kidney development, but not in the adult kidney as previously reported 23, 25 . Therefore, we targeted constitutive knockdown of Klf15 in Foxd1+ cells using the Cre-loxP recombination system by crossing the Foxd1-Cre (C57BL/6) mice with Klf15 fl/fl (C57BL/6) mice to generate Foxd1-Cre Klf15 fl/fl mice (F2).…”

Section: Resultssupporting

confidence: 61%

The loss of Krüppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis

Mallipattu

Guo

et al. 2017

Kidney International

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Large epidemiological studies clearly demonstrate that multiple episodes of acute kidney injury contribute to the development and progression of kidney fibrosis. Although our understanding of kidney fibrosis has improved in the past two decades, we have limited therapeutic strategies to halt its progression. Myofibroblast differentiation and proliferation remain critical to progression of kidney fibrosis. Although canonical Wnt signaling can trigger activation of myofibroblasts in the kidney, mediators of Wnt inhibition in the resident progenitor cells are unclear. Recent studies demonstrate that the loss of a Kruppel-Like Factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, exacerbates kidney fibrosis in murine models. Here, we tested whether Klf15 mRNA and protein expression is reduced in late stages of fibrosis in mice that underwent unilateral ureteric obstruction, a model of progressive renal fibrosis Knockdown of Klf15 in Foxd1-expressing cells (Foxd1-Cre Klf15fl/fl) increased extracellular matrix deposition and myofibroblast proliferation as compared to wildtype (Foxd1-Cre Klf15+/+) mice after three and seven days of ureteral obstruction. This was validated in mice receiving angiotensin II treatment for six weeks. In both these murine models, the increase in renal fibrosis was found in Foxd1-Cre Klf15fl/fl mice and accompanied by activation of Wnt/β-catenin signaling. Furthermore, knockdown of Klf15 in cultured mouse embryonic fibroblasts activated canonical Wnt/β-catenin signaling, increased profibrotic transcripts, and increased proliferation after treatment with a Wnt1 ligand. Conversely, overexpression of KLF15 inhibited phospho-β-catenin (Ser552) expression in Wnt1-treated cells. Thus, KLF15 has a critical role in attenuating kidney fibrosis by inhibiting the canonical Wnt/β-catenin pathway.

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“…We also establish that PHD3, but not PHD1 (data not shown), is capable of suppressing HIF-α stabilization in a large subpopulation of Phd2 −/− interstitial cells, as Foxd1-Phd2 −/− - Phd3 −/− mutants were characterized by a significant increase in the number of stromal cells with stabilized HIF-α compared to Foxd1-Phd2 −/− mutants. Differential sensitivity of renal stroma to genetic Phd2 deletion may be due to differences in PHD3 expression levels as previously suggested, 26 which may indicate that renal interstitial cells display differential responsiveness to hypoxia. 39, 41 …”

Section: Discussionmentioning

confidence: 59%

“…Vascular changes in Foxd1-Phd2 −/− - Phd3 −/− kidneys were associated with increased transcription of vascular endothelial growth factor (Vegf) in renal interstitium as demonstrated by fluorescent RNA in situ hybridization (RNA-FISH, data not shown), which is consistent with findings in adult Foxd1-Phd2 −/− mice. 26 Differences in Acta2 mRNA expression were not observed. Taken together our data demonstrate that inactivation of both PHD2 and PHD3 in stromal cells resulted in interstitial HIF activation, which led to renal failure and was associated with juvenile lethality.…”

Section: Resultsmentioning

confidence: 93%

“…This was associated with increased Epo and Vegf transcription, and suggested that renal interstitial cells were heterogeneous with regard to their responsiveness to PHD2 inactivation. 26 Although HIF prolyl-4-hydroxylases regulate the activity of both HIF-1α and HIF-2α, HIF-1α was not detectable in adult Foxd1-Phd2 −/− kidneys. To examine whether HIF-1α was expressed in renal stroma during development, we used IHC to investigate the cellular and spatial distribution of HIF-1α and HIF-2α in kidneys from newborn Cre − control, Foxd1-Phd2 −/− and Foxd1-Phd2 −/− - Phd3 −/− mice.…”

Section: Resultsmentioning

confidence: 97%

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Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development

Kobayashi

Liu

Urrutia

et al. 2017

Kidney International

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Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight and multiple organ defects. In the kidney this can lead to low nephron endowment predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2 and PHD3. In the adult kidney PHD oxygen-sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.

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Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin

Cited by 93 publications

References 55 publications

Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements

Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements

The loss of Krüppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis

Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development

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