Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice

Fuchs, Michaela; Broeker, Katharina; Schrankl, Julia; Burzlaff, Nicolai; Willam, Carsten; Wagner, Charlotte; Kurtz, Armin

doi:10.1016/j.kint.2021.02.035

Cited by 22 publications

(14 citation statements)

References 69 publications

(140 reference statements)

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“…In the murine model of early renal fibrosis at day 4 after UUO surgery, we demonstrated that SB431542 could reverse Epo expression in the UUO kidney myofibroblasts through inhibiting TGF-β1-activated ALK5. Our finding could be supported by the recent report that selective disruption of TGF-βR2 in renal PDGFRβ + cells preserves EPO production but no discernible effect on myofibroblast markers in the murine model of renal fibrosis [ 46 ].…”

Section: Discussionsupporting

confidence: 86%

Transforming growth factor-β1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells

Shih

Pan

et al. 2021

J Biomed Sci

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Background Renal erythropoietin (EPO)-producing (REP) cells produce EPO through hypoxia-inducible factor (HIF) 2α-activated gene transcription. Insufficient EPO production leads to anemia in patients with chronic kidney disease. Although recombinant EPO is effective to improve anemia, no reliable REP cell lines limit further progress of research and development of novel treatment. Methods We screened Epo mRNA expression in mouse fibroblast cell lines. Small interfering RNA specific for HIF1α or HIF2α was transfected to study Epo expression in C3H10T1/2 cells. The effect of transforming growth factor-β1 (TGF-β1) on HIF-EPO axis was studied in C3H10T1/2 cells and mice. Results Similar to mouse REP pericytes, C3H10T1/2 cells differentiated to α-smooth muscle actin+ myofibroblasts after exposure to TGF-β1. Specific HIF knockdown demonstrated the role of HIF2α in hypoxia-induced Epo expression. Sustained TGF-β1 exposure increased neither DNA methyltransferase nor methylation of Epas1 and Epo genes. However, TGF-β1 repressed HIF2α-encoding Epas1 promptly through activating activin receptor-like kinase-5 (ALK5), thereby decreasing Epo induction by hypoxia and prolyl hydroxylase domain inhibitor roxadustat. In mice with pro-fibrotic injury induced by ureteral obstruction, upregulation of Tgfb1 was accompanied with downregulation of Epas1 and Epo in injured kidneys and myofibroblasts, which were reversed by ALK5 inhibitor SB431542. Conclusion C3H10T1/2 cells possessed the property of HIF2α-dependent Epo expression in REP pericytes. TGF-β1 induced not only the transition to myofibroblasts but also a repressive effect on Epas1-Epo axis in C3H10T1/2 cells. The repressive effect of TGF-β1 on Epas1-Epo axis was confirmed in REP pericytes in vivo. Inhibition of TGF-β1-ALK5 signaling might provide a novel treatment to rescue EPO expression in REP pericytes of injured kidney.

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Section: Discussionsupporting

confidence: 86%

Transforming growth factor-β1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells

Shih

Pan

et al. 2021

J Biomed Sci

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“…Notably, suppression of NFκB signaling with glucocorticoids and genetic disruption of TGFB1 receptor 2 function can protect from loss of EPO production in injured kidneys. 4,32,34 Furthermore, epigenetic reprogramming is likely to play an important role in EPO regulation during kidney disease progression. An increase in the expression of DNA methyl transferases and hypermethylation of Epo 5′-regulatory elements F I G U R E 7 Stimulation of EPO synthesis in fibrotic kidneys following pharmacologic HIF-PHD inhibition.…”

Section: Discussionmentioning

confidence: 99%

EPO synthesis induced by HIF‐PHD inhibition is dependent on myofibroblast transdifferentiation and colocalizes with non‐injured nephron segments in murine kidney fibrosis

et al. 2022

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Aim Erythropoietin (EPO) is regulated by hypoxia‐inducible factor (HIF)‐2. In the kidney, it is produced by cortico‐medullary perivascular interstitial cells, which transdifferentiate into collagen‐producing myofibroblasts in response to injury. Inhibitors of prolyl hydroxylase domain (PHD) dioxygenases (HIF‐PHIs) activate HIF‐2 and stimulate kidney and liver EPO synthesis in patients with anemia of chronic kidney disease (CKD). We examined whether HIF‐PHIs can reactivate EPO synthesis in interstitial cells that have undergone myofibroblast transdifferentiation in established kidney fibrosis. Methods We investigated Epo transcription in myofibroblasts and characterized the histological distribution of kidney Epo transcripts by RNA in situ hybridization combined with immunofluorescence in mice with adenine nephropathy (AN) treated with HIF‐PHI molidustat. Lectin absorption chromatography was used to assess liver‐derived EPO. In addition, we examined kidney Epo transcription in Phd2 knockout mice with obstructive nephropathy. Results In AN, molidustat‐induced Epo transcripts were not found in areas of fibrosis and did not colocalize with interstitial cells that expressed α‐smooth muscle actin, a marker of myofibroblast transdifferentiation. Epo transcription was associated with megalin‐expressing, kidney injury molecule 1‐negative nephron segments and contingent on residual renal function. Liver‐derived EPO did not contribute to serum EPO in molidustat‐treated mice. Epo transcription was not associated with myofibroblasts in Phd2 knockout mice with obstructive nephropathy. Conclusions Our studies suggest that HIF‐PHIs do not reactivate Epo transcription in interstitial myofibroblasts and that their efficacy in inducing kidney EPO in CKD is dependent on the degree of myofibroblast formation, the preservation of renal parenchyma and the level of residual renal function.

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“…In this hypothetical model, renal "microenvironmental relative hyperoxia" is caused by decreased oxygen consumption of damaged tubules during the course of the disease, which leads to an attenuated hemoglobin oxygen desaturation of the capillary blood in the vicinity of the pericytic Epo-producing (REP) cells. Consequently, intracellular pO 2 levels in REP cells exceed the normal hypoxic set point required for Epo production, leading to renal anemia expression in ESRD [35]. Of note, TGFβ has recently been shown to suppress HIF-2α and Epo expression [96], which may thus represent a transdifferentiation-independent direct function of the TGFβ pathway.…”

Section: Why Do Rep Cells Fail To Produce Epo In Chronic Kidney Disease?mentioning

confidence: 99%

Fount, fate, features, and function of renal erythropoietin-producing cells

Dahl

Bapst

Khodo

et al. 2022

Pflugers Arch - Eur J Physiol

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Renal erythropoietin (Epo)-producing (REP) cells represent a rare and incompletely understood cell type. REP cells are fibroblast-like cells located in close proximity to blood vessels and tubules of the corticomedullary border region. Epo mRNA in REP cells is produced in a pronounced “on–off” mode, showing transient transcriptional bursts upon exposure to hypoxia. In contrast to “ordinary” fibroblasts, REP cells do not proliferate ex vivo, cease to produce Epo, and lose their identity following immortalization and prolonged in vitro culture, consistent with the loss of Epo production following REP cell proliferation during tissue remodelling in chronic kidney disease. Because Epo protein is usually not detectable in kidney tissue, and Epo mRNA is only transiently induced under hypoxic conditions, transgenic mouse models have been developed to permanently label REP cell precursors, active Epo producers, and inactive descendants. Future single-cell analyses of the renal stromal compartment will identify novel characteristic markers of tagged REP cells, which will provide novel insights into the regulation of Epo expression in this unique cell type.

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Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice

Abstract: Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice.

Cited by 22 publications

References 69 publications

Transforming growth factor-β1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells

Transforming growth factor-β1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells

EPO synthesis induced by HIF‐PHD inhibition is dependent on myofibroblast transdifferentiation and colocalizes with non‐injured nephron segments in murine kidney fibrosis

Fount, fate, features, and function of renal erythropoietin-producing cells

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