Generation of renal Epo-producing cell lines by conditional gene tagging reveals rapid HIF-2 driven Epo kinetics, cell autonomous feedback regulation, and a telocyte phenotype.

Abstract:

:Erythropoietin (Epo) is essential for erythropoiesis and is mainly produced by the fetal liver and the adult kidney following hypoxic stimulation. Epo regulation is commonly studied in hepatoma cell lines, but differences in Epo regulation between kidney and liver limit the understanding of Epo dysregulation in polycythaemia and anaemia. To overcome this limitation, we have generated a novel transgenic mouse model expressing Cre recombinase specifically in the active fraction of renal Epo-producing (REP) cells. Crossing with reporter mice confirmed the inducible and highly specific tagging of REP cells, located in the corticomedullary border region where there is a steep drop in oxygen bioavailability. A novel method was developed to selectively grow primary REP cells in culture and to generate immortalized clonal cell lines, called fibroblastoid atypical interstitial kidney (FAIK) cells. FAIK cells show very early hypoxia-inducible factor (HIF)-2α induction, which precedes Epo transcription. Epo induction in FAIK cells reverses rapidly despite ongoing hypoxia, suggesting a cell autonomous feedback mechanism. In contrast, HIF stabilizing drugs resulted in chronic Epo induction in FAIK cells. RNA sequencing of three FAIK cell lines derived from independent kidneys revealed a high degree of overlap and suggests that REP cells represent a unique cell type with properties of pericytes, fibroblasts, and neurons, known as telocytes. These novel cell lines may be helpful to investigate myofibroblast differentiation in chronic kidney disease and to elucidate the molecular mechanisms of HIF stabilizing drugs currently in phase III studies to treat anemia in end-stage kidney disease.

journal_name

Kidney Int

journal_title

Kidney international

authors

Imeri F,Nolan KA,Bapst AM,Santambrogio S,Abreu-Rodríguez I,Spielmann P,Pfundstein S,Libertini S,Crowther L,Orlando IMC,Dahl SL,Keodara A,Kuo W,Kurtcuoglu V,Scholz CC,Qi W,Hummler E,Hoogewijs D,Wenger RH

doi

10.1016/j.kint.2018.08.043

subject

Has Abstract

pub_date

2019-02-01 00:00:00

pages

375-387

issue

2

eissn

0085-2538

issn

1523-1755

pii

S0085-2538(18)30673-2

journal_volume

95

pub_type

杂志文章
  • Prognostically controlled comparison of dialysis and renal transplantation.

    abstract::Because the comparison of survival in patients with renal failure treated by dialysis and transplantation may be biased by pretreatment prognostic differences in the patients who receive these two therapies, we quantified the pretreatment prognosis of all 430 dialysis and transplant patients who began therapy for end-...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1984.132

    authors: Hutchinson TA,Thomas DC,Lemieux JC,Harvey CE

    更新日期:1984-07-01 00:00:00

  • Urinary CCN2 (CTGF) as a possible predictor of diabetic nephropathy: preliminary report.

    abstract:BACKGROUND:It is currently impossible to reliably predict which diabetic patients will develop nephropathy and progress to kidney failure. Microalbuminuria, often regarded as a predictor of overt diabetic renal disease is, in fact, an indicator of established glomerular damage. We have shown that glomerular expression ...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1046/j.1523-1755.2003.00130.x

    authors: Riser BL,Cortes P,DeNichilo M,Deshmukh PV,Chahal PS,Mohammed AK,Yee J,Kahkonen D

    更新日期:2003-08-01 00:00:00

  • Treatment of experimental renal osteodystrophy with pamidronate.

    abstract::We evaluated the effects of the bisphosphonate pamidronate on bone histomorphometry, structure and strength in male rats with uninephrectomy or with chronic renal disease induced by 5/6 nephrectomy. In rats with chronic renal disease the plasma urea, phosphate and parathyroid hormone levels were significantly increase...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.2008.180

    authors: Jokihaara J,Pörsti IH,Kööbi P,Jolma PM,Mustonen JT,Saha HH,Sievänen H,Kannus P,Iwaniec UT,Turner RT,Järvinen TL

    更新日期:2008-08-01 00:00:00

  • Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury.

    abstract::Podocyte injury and loss contribute to the progression of glomerular diseases, including diabetic kidney disease. We previously found that the glomerular expression of Sirtuin-1 (SIRT1) is reduced in human diabetic glomeruli and that the podocyte-specific loss of SIRT1 aggravated albuminuria and worsened kidney diseas...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1016/j.kint.2017.12.008

    authors: Hong Q,Zhang L,Das B,Li Z,Liu B,Cai G,Chen X,Chuang PY,He JC,Lee K

    更新日期:2018-06-01 00:00:00

  • Improvement of growth and food utilization by human recombinant growth hormone in uremia.

    abstract::We compared growth rate, food conversion ratio and morphology of the growth zone in female Sprague-Dawley rats with subtotal nephrectomy or sham operation. Both groups were either given vehicle or 1.4 IU/day recombinant human growth hormone (GH) by s.c. osmotic minipump, or 2.5 IU twice daily intraperitoneally for 14 ...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1988.7

    authors: Mehls O,Ritz E,Hunziker EB,Eggli P,Heinrich U,Zapf J

    更新日期:1988-01-01 00:00:00

  • Reduced human transitional B cell T1/T2 ratio is associated with subsequent deterioration in renal allograft function.

    abstract::Human transitional B cells express relatively high IL-10 and low TNF-α levels, which correlate with B regulatory activity in vitro. Herein, we aim to further define B regulatory phenotype and determine whether B regulatory activity can serve as a prognostic marker for renal allograft dysfunction (graft loss or 2-fold ...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1016/j.kint.2016.08.028

    authors: Cherukuri A,Salama AD,Carter CR,Landsittel D,Arumugakani G,Clark B,Rothstein DM,Baker RJ

    更新日期:2017-01-01 00:00:00

  • Mechanisms of fluid secretion by polycystic epithelia.

    abstract::We have sought to determine the mechanisms driving fluid secretion by the cystic epithelium in autosomal dominant polycystic kidney disease (ADPKD). We have performed in vitro experiments on intact cysts dissected from discarded ADPKD kidneys, on monolayers of cells cultured from the cystic epithelium and on microcyst...

    journal_title:Kidney international

    pub_type: 杂志文章,评审

    doi:10.1038/ki.1996.230

    authors: Sullivan LP,Grantham JJ

    更新日期:1996-06-01 00:00:00

  • Immunological quantification of advanced glycosylation end-products in the serum of patients on hemodialysis or CAPD.

    abstract::We have developed an immunological procedure for measuring advanced glycosylation end-products (AGEs) in serum. Using this method, we measured AGEs in healthy volunteers, patients with diabetes, renal failure without treatment and in patients with renal failure, treated with hemodialysis (HD) or continuous ambulatory ...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1994.262

    authors: Papanastasiou P,Grass L,Rodela H,Patrikarea A,Oreopoulos D,Diamandis EP

    更新日期:1994-07-01 00:00:00

  • Identification of antigenic epitopes in type IV collagen by use of synthetic peptides.

    abstract::Peptides representing potential antigenic regions of the NC-1 and 7-S domains of the human alpha 1 and alpha 2, and bovine alpha 3 chains of type IV collagen were synthesized either chemically or by the recombinant DNA technique and tested by ELISA using antibodies raised in rabbits against the whole type IV collagen ...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1993.16

    authors: Kefalides NA,Ohno N,Wilson CB,Fillit H,Zabriski J,Rosenbloom J

    更新日期:1993-01-01 00:00:00

  • Adenosine induces mesangial cell contraction by an A1-type receptor.

    abstract::Adenosine is known to decrease renal blood flow and glomerular filtration rate. We have tested the hypothesis that adenosine exerts contractile effects on mesangial cells. Furthermore, we have studied, using selective agonists and antagonists for adenosine, which kind of adenosine receptor, A1 or A2, is mainly implica...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1989.126

    authors: Olivera A,Lamas S,Rodriguez-Puyol D,López-Novoa JM

    更新日期:1989-06-01 00:00:00

  • Captopril inhibits the agonist-induced increase of cytosolic free Ca2+ in glomerular mesangial cells.

    abstract::To evaluate the underlying mechanism of the putative renal protective effects of angiotensin converting enzyme (ACE) inhibitors, the modulatory action of captopril on the angiotensin II (Ang II) and platelet-derived growth factor (PDGF)-induced increase of cytosolic free calcium concentration ([Ca2+]i) was investigate...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1994.323

    authors: Tepel M,Heidenreich S,Zhu Z,Walter M,Nofer JR,Zidek W

    更新日期:1994-09-01 00:00:00

  • The intrinsic prostaglandin E2-EP4 system of the renal tubular epithelium limits the development of tubulointerstitial fibrosis in mice.

    abstract::Inflammatory responses in the kidney lead to tubulointerstitial fibrosis, a common feature of chronic kidney diseases. Here we examined the role of prostaglandin E(2) (PGE(2)) in the development of tubulointerstitial fibrosis. In the kidneys of wild-type mice, unilateral ureteral obstruction leads to progressive tubul...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.2012.115

    authors: Nakagawa N,Yuhki K,Kawabe J,Fujino T,Takahata O,Kabara M,Abe K,Kojima F,Kashiwagi H,Hasebe N,Kikuchi K,Sugimoto Y,Narumiya S,Ushikubi F

    更新日期:2012-07-01 00:00:00

  • Tissue engineering of a bioartificial renal tubule assist device: in vitro transport and metabolic characteristics.

    abstract:BACKGROUND:Current renal substitution therapy for acute or chronic renal failure with hemodialysis or hemofiltration is life sustaining, but continues to have unacceptably high morbidity and mortality rates. This therapy is not complete renal replacement therapy because it does not provide active transport nor metaboli...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1046/j.1523-1755.1999.00486.x

    authors: Humes HD,MacKay SM,Funke AJ,Buffington DA

    更新日期:1999-06-01 00:00:00

  • Dysregulation of cytokine expression in tubulointerstitial nephritis associated with murine malaria.

    abstract::We examined the circulating levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 alpha, IL-6, granulocyte macrophage-colony stimulating factor (GM-CSF), and the anti-inflammatory cytokine IL-10, and their expression in kidneys acutely infected with murine malaria parasite...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1111/j.1523-1755.1998.00848.x

    authors: Rui-Mei L,Kara AU,Sinniah R

    更新日期:1998-04-01 00:00:00

  • Differential expression of Cux-1 and p21 in polycystic kidneys from Pkd1 null and cpk mice.

    abstract:BACKGROUND:Cux-1 is a murine homeodomain protein that functions as a cell cycle-dependent transcriptional repressor in proliferating cells. Targets of Cux-1 repression include the cyclin kinase inhibitors p21 and p27. In the kidney, Cux-1 is spatially and temporally regulated, and ectopic expression of Cux-1 in transge...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1111/j.1523-1755.2005.67099.x

    authors: Sharma M,Brantley JG,Alcalay NI,Zhou J,Heystek E,Maser RL,Vanden Heuvel GB

    更新日期:2005-02-01 00:00:00

  • Cyclosporine induces elevated procollagen alpha 1 (I) mRNA levels in the rat renal cortex.

    abstract::Chronic cyclosporine nephrotoxicity is a poorly understood drug side-effect characterized by renal cortical interstitial scarring. To evaluate procollagen mRNA levels as an early factor in the development of this form of renal fibrosis, we measured renal procollagen alpha 1 (I), alpha 1 (III), alpha 1 (IV) and beta-ac...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1991.75

    authors: Nast CC,Adler SG,Artishevsky A,Kresser CT,Ahmed K,Anderson PS

    更新日期:1991-04-01 00:00:00

  • Time to consider ACE insertion/deletion genotypes and individual renoprotective treatment in diabetic nephropathy?

    abstract::One reason for the inadequacy of current renoprotective therapy and the persistent poor renal prognosis in diabetic nephropathy is the large interindividual variation in response to treatment. Genetic as well as non-genetic factors are known to influence treatment efficacy. This Commentary summarizes the impact of the...

    journal_title:Kidney international

    pub_type: 评论,杂志文章

    doi:10.1038/sj.ki.5000283

    authors: Jacobsen PK,Tarnow L,Parving HH

    更新日期:2006-04-01 00:00:00

  • Renal anaphylaxis. I. Antigen-initiated responses from isolated perfused rat kidney.

    abstract::Isolated perfused rat kidneys were passively sensitized by addition of either mouse ascitic fluid containing monoclonal IgE against dinitrophenol (DNP) or DNP-specific purified IgE. After washing the organ, defined doses of DNP-bovine serum albumin were given as bolus injection via the kidney artery. Antigen challenge...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1987.197

    authors: Pirotzky E,Pintos-Morell G,Burtin C,Boudet J,Bidault J,Benveniste J

    更新日期:1987-08-01 00:00:00

  • Surface areas of brush border and lateral cell walls in the rabbit proximal nephron.

    abstract::A morphometric technique is used to estimate the absolute and relative surface areas of the brush border microvilli and cell walls bordering lateral intercellular spaces. In isolated, perfused proximal tubule from rabbit, the luminal and lateral surfaces are equal in area. For proximal convoluted tubules (PCT) each su...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1975.125

    authors: Welling LW,Welling DJ

    更新日期:1975-12-01 00:00:00

  • Immunolocalization of NAD-dependent 11 beta-hydroxysteroid dehydrogenase in human kidney and colon.

    abstract::The inactivation of physiological glucocorticoids by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) confers mineralocorticoid specificity to certain aldosterone target tissues. Both NADP, and NAD-dependent isoforms of 11 beta-HSD have been described. An NAD-dependent isoform of 11 beta-HSD (11 beta-HSD2) was recen...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1996.39

    authors: Kyossev Z,Walker PD,Reeves WB

    更新日期:1996-01-01 00:00:00

  • Regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF-A) expression in podocytes.

    abstract:BACKGROUND:Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF-A) is expressed constitutively in the adult glomerular podocytes at high levels; however, the regulation of its production is unclear. Recent data from podocyte-specific knockout mice suggest that VPF/VEGF-A is critical for the proper ...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1111/j.1523-1755.2004.00910.x

    authors: Datta K,Li J,Karumanchi SA,Wang E,Rondeau E,Mukhopadhyay D

    更新日期:2004-10-01 00:00:00

  • The International Pediatric Peritonitis Registry: starting to walk.

    abstract::The International Pediatric Peritonitis Registry (IPPR) was created to assess and evaluate the validity of the pediatric peritonitis treatment guidelines issued by the International Society for Peritoneal Dialysis. The study by Schaefer et al., one of the first to emerge from the IPPR, describes regional variability i...

    journal_title:Kidney international

    pub_type: 评论,杂志文章

    doi:10.1038/sj.ki.5002529

    authors: Teitelbaum I

    更新日期:2007-12-01 00:00:00

  • Breaking the ice: urine proteomics of medullary sponge kidney disease.

    abstract::Urinary proteomics is a promising tool for biomarker investigation, particularly in complex kidney diseases. Fabris and colleagues report that urinary laminin subunit alpha-2 is a potential diagnostic marker of medullary sponge kidney (MSK) disease by using a label-free quantitative proteomics platform and a clinicall...

    journal_title:Kidney international

    pub_type: 评论,杂志文章

    doi:10.1016/j.kint.2016.10.032

    authors: Chutipongtanate S

    更新日期:2017-02-01 00:00:00

  • Renal tubular transport of gentamicin in the rat.

    abstract::The renal handling of gentamicin in the rat was examined by clearance, microinjection, and renal cortical-slice techniques. The steady-state renal clearance of 14C-gentamicin, when corrected for the 7.5% binding to plasma protein, was not significantly different from that of 3H-inulin. At the end of the renal clearanc...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1979.149

    authors: Pastoriza-Munoz E,Bowman RL,Kaloyanides GJ

    更新日期:1979-10-01 00:00:00

  • Mechanisms of the proteinuria induced by Rho GTPases.

    abstract::Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.2011.472

    authors: Wang L,Ellis MJ,Gomez JA,Eisner W,Fennell W,Howell DN,Ruiz P,Fields TA,Spurney RF

    更新日期:2012-06-01 00:00:00

  • Parenteral iron treatment induces MCP-1 accumulation in plasma, normal kidneys, and in experimental nephropathy.

    abstract:INTRODUCTION:Monocyte chemoattractant protein-1 (MCP-1) promotes renal inflammation, thereby contributing to acute and chronic nephropathies. Its production is stimulated by oxidative stress. Thus, this study tested whether pro-oxidant iron/carbohydrate complexes, used to treat iron deficiency, induce MCP-1 in renal/ex...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1111/j.1523-1755.2005.00565.x

    authors: Zager RA

    更新日期:2005-10-01 00:00:00

  • Dietary potassium influences kidney maintenance of serum phosphorus concentration.

    abstract::In studying the metabolic effects of diet potassium (K+) variation in normal humans, we noted that varying diet K+ within its normal range influenced inorganic phosphorus (Pi) homeostasis and serum calcitriol (1,25-dihydroxyvitamin D) levels. In six men who ingested a constant whole-foods diet containing (per 70 kg bo...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1990.120

    authors: Sebastian A,Hernandez RE,Portale AA,Colman J,Tatsuno J,Morris RC Jr

    更新日期:1990-05-01 00:00:00

  • Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism.

    abstract:BACKGROUND:In uremic patients with secondary hyperparathyroidism (2HPT), nodular hyperplasia of parathyroid gland shows a monoclonal pattern of cell proliferation, in which a decreased density of vitamin D receptor (VDR) also is demonstrated. The present study aimed at elucidating the mechanism of parathyroid cell prol...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1111/j.1523-1755.2002.kid585.x

    authors: Tokumoto M,Tsuruya K,Fukuda K,Kanai H,Kuroki S,Hirakata H

    更新日期:2002-10-01 00:00:00

  • Expression of leucocyte and lymphocyte adhesion molecules in the human kidney.

    abstract::Leucocyte interaction with other cells is facilitated by the adhesion molecules, leucocyte function-associated antigen-1 (LFA-1)-binding to intercellular adhesion molecule-1 (ICAM-1) and for T cells and natural killer (NK) cells the binding of LFA-2 (CD2) to LFA-3. As these interactions are critical for the mediation ...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1989.303

    authors: Bishop GA,Hall BM

    更新日期:1989-12-01 00:00:00

  • Autonomic blockade and the Valsalva maneuver in patients on maintenance hemodialysis: a hemodynamic study.

    abstract::Hemodynamic studies were performed at two levels of dietary sodium intake (10 mmoles/day and 100 mmoles/day for 14 days) in a group of patients (with retained kidneys) on chronic hemodialysis. Plasma renin activity and aldosterone, plasma, and extracellular fluid (ECF) volumes were measured while the patient were at r...

    journal_title:Kidney international

    pub_type: 杂志文章

    doi:10.1038/ki.1977.114

    authors: McGrath BP,Tiller DJ,Bune A,Chalmers JP,Korner PI,Uther JB

    更新日期:1977-10-01 00:00:00