Citations to this article
Sierra S. Marable, … , S. Steven Potter, Joo-Seop Park
Published July 25, 2018
Citation Information: JCI Insight. 2018;3(14):e97497. https://doi.org/10.1172/jci.insight.97497.
Citation Information: JCI Insight. 2018;3(14):e97497. https://doi.org/10.1172/jci.insight.97497.
Abstract
Different nephron tubule segments perform distinct physiological functions, collectively acting as a blood filtration unit. Dysfunction of the proximal tubule segment can lead to Fanconi renotubular syndrome (FRTS), with major symptoms such as excess excretion of water, glucose, and phosphate in the urine. It has been shown that a mutation in HNF4A is associated with FRTS in humans and that Hnf4a is expressed specifically in proximal tubules in adult rat nephrons. However, little is known about the role of Hnf4a in nephrogenesis. Here, we found that Hnf4a is expressed in both presumptive and differentiated proximal tubules in the developing mouse kidney. We show that Hnf4a is required for the formation of differentiated proximal tubules but is dispensable for the formation of presumptive proximal tubules. Furthermore, we show that loss of Hnf4a decreased the expression of proximal tubule–specific genes. Adult Hnf4a mutant mice presented with FRTS-like symptoms, including polyuria, polydipsia, glycosuria, and phosphaturia. Analysis of the adult Hnf4a mutant kidney also showed proximal tubule dysgenesis and nephrocalcinosis. Our results demonstrate the critical role of Hnf4a in proximal tubule development and provide mechanistic insight into the etiology of FRTS.
Authors
Sierra S. Marable, Eunah Chung, Mike Adam, S. Steven Potter, Joo-Seop Park
Citation information
Citations to this article (37)
| Title and authors | Publication | Year |
|---|---|---|
|
The thin descending limb of the loop of Henle originates from proximal tubule cells during mouse kidney development
Chung E, Nosrati F, Adam M, Potter A, Sayed M, Humphreys BD, Lim HW, Hu YC, Potter SS, Park JS |
bioRxiv | 2025 |
|
Uncovering Potential Biomarkers and Constructing a Prediction Model Associated with Iron Metabolism in Parkinson’s Disease
Cheng Y, Zhai H, Liu Y, Yang Y, Fang B, Song M, Zhong P |
Neuropsychiatric Disease and Treatment | 2025 |
|
Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population
Michalopulos MG, Liu Y, Raju DR, Lafin JT, Ma Y, Gaur D, Khadka S, Xing C, McMahon AP, Carroll TJ, Drake KA |
bioRxiv | 2025 |
|
Lysine-specific demethylase 1a is obligatory for gene regulation during kidney development
Kota SB, Kota SK |
bioRxiv | 2025 |
|
HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements
Thakur A, Park K, Cullum R, Fuglerud BM, Khoshnoodi M, Drissler S, Stephan TL, Lotto J, Kim D, Gonzalez FJ, Hoodless PA |
Communications biology | 2024 |
|
Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model
Lee JE, Kim JY, Leem J |
Molecules (Basel, Switzerland) | 2024 |
|
Plasma Proteins Associated with Chronic Histopathologic Lesions on Kidney Biopsy
Kim T, Surapaneni AL, Schmidt IM, Eadon MT, Kalim S, Srivastava A, Palsson R, Stillman IE, Hodgin JB, Menon R, Otto EA, Coresh J, Grams ME, Waikar SS, Rhee EP |
Journal of the American Society of Nephrology : JASN | 2024 |
|
Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function
Loeb GB, Kathail P, Shuai R, Chung R, Grona RJ, Peddada S, Sevim V, Federman S, Mader K, Chu A, Davitte J, Du J, Gupta AR, Ye CJ, Shafer S, Przybyla L, Rapiteanu R, Ioannidis N, Reiter JF |
2024 | |
|
Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function.
Loeb GB, Kathail P, Shuai RW, Chung R, Grona RJ, Peddada S, Sevim V, Federman S, Mader K, Chu AY, Davitte J, Du J, Gupta AR, Ye CJ, Shafer S, Przybyla L, Rapiteanu R, Ioannidis NM, Reiter JF |
Nature genetics | 2024 |
|
TNIK depletion induces inflammation and apoptosis in injured renal proximal tubule epithelial cells
Bradford ST, Wu H, Kirita Y, Chen C, Malvin NP, Yoshimura Y, Muto Y, Humphreys BD |
American Journal of Physiology - Renal Physiology | 2024 |
|
Hepatocyte Nuclear Factor 4 alpha 2 is a novel osteoblast transcription factor that regulates osteogenesis
Marta Martinez-Calle, Guillaume Courbon, Bridget Hunt-Tobey, Connor Francis, Jadeah Spindler, Xueyan Wang, Luciene M. dos Reis, Carolina Steller Wagner Martins, Isidro Salusky, Hartmut H Malluche, Thomas L Nickolas, Rosa M.A. Moyses, Aline Martin, Valentin David |
Journal of Clinical Investigation | 2023 |
|
Transcription factor c-Maf deletion improves streptozotocin-induced diabetic nephropathy by directly regulating Sglt2 and Glut2
Mitsunori Fujino, Naoki Morito, Takuto Hayashi, Masami Ojima, Shun Ishibashi, Akihiro Kuno, Seizo Koshiba, Kunihiro Yamagata, Satoru Takahashi |
JCI Insight | 2023 |
|
A single-cell multiomic analysis of kidney organoid differentiation
Yoshimura Y, Muto Y, Ledru N, Wu H, Omachi K, Miner JH, Humphreys BD |
Proceedings of the National Academy of Sciences | 2023 |
|
Identification and validation of NFIA as a novel prognostic marker in renal cell carcinoma.
de Alwis R, Schoch S, Islam M, Möller C, Ljungberg B, Axelson H |
2023 | |
|
Renal Fanconi syndrome and hypoglycemia: lessons for clinical nephrologists.
Aksenova M, Zaikova N, Tozliyan E |
Journal of Nephrology | 2023 |
|
Expanding the p.(Arg85Trp) Variant-Specific Phenotype of HNF4A: Features of Glycogen Storage Disease, Liver Cirrhosis, Impaired Mitochondrial Function, and Glomerular Changes
Grassi M, Laubscher B, Pandey AV, Tschumi S, Graber F, Schaller A, Janner M, Aeberli D, Hewer E, Nuoffer JM, Gautschi M |
Molecular syndromology | 2023 |
|
Elucidating the Proximal Tubule HNF4A Gene Regulatory Network in Human Kidney Organoids
Yoshimura Y, Muto Y, Omachi K, Miner JH, Humphreys BD |
Journal of the American Society of Nephrology : JASN | 2023 |
|
RAAS-deficient organoids indicate delayed angiogenesis as a possible cause for autosomal recessive renal tubular dysgenesis.
Pode-Shakked N, Slack M, Sundaram N, Schreiber R, McCracken KW, Dekel B, Helmrath M, Kopan R |
Nature Communications | 2023 |
|
A potent HNF4α agonist reveals that HNF4α controls genes important in inflammatory bowel disease and Paneth cells
S Lee, V Veeriah, F Levine, P Dudeja |
PloS one | 2022 |
|
The dynamic effect of genetic variation on the in vivo ER stress transcriptional response in different tissues
Russell ND, Chow CY |
G3: Genes|Genomes|Genetics | 2022 |
|
Single-Cell Chromatin and Gene-Regulatory Dynamics of Mouse Nephron Progenitors.
Hilliard S, Tortelote G, Liu H, Chen CH, El-Dahr SS |
Journal of the American Society of Nephrology : JASN | 2022 |
|
Renal oncometabolite L-2-hydroxyglutarate imposes a block in kidney tubulogenesis: Evidence for an epigenetic basis for the L-2HG-induced impairment of differentiation
Taub M, Mahmoudzadeh NH, Tennessen JM, Sudarshan S |
Frontiers in Endocrinology | 2022 |
|
A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery
Tran T, Song CJ, Nguyen T, Cheng SY, McMahon JA, Yang R, Guo Q, Der B, Lindström NO, Lin DC, McMahon AP |
Cell Stem Cell | 2022 |
|
Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair
S Ide, Y Kobayashi, K Ide, SA Strausser, K Abe, S Herbek, LL O'Brien, SD Crowley, L Barisoni, A Tata, PR Tata, T Souma |
eLife | 2021 |
|
Loss of proximal tubular transcription factor Krüppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation
SE Piret, AA Attallah, X Gu, Y Guo, NA Gujarati, J Henein, A Zollman, T Hato, A Maayan, MP Revelo, KG Dickman, CH Chen, CT Shun, TA Rosenquist, JC He, SK Mallipattu |
Kidney International | 2021 |
|
Chromatin-accessibility estimation from single-cell ATAC-seq data with scOpen
Z Li, C Kuppe, S Ziegler, M Cheng, N Kabgani, S Menzel, M Zenke, R Kramann, IG Costa |
Nature Communications | 2021 |
|
The nuclear receptor HNF4 drives a brush border gene program conserved across murine intestine, kidney, and embryonic yolk sac
L Chen, S Luo, A Dupre, RP Vasoya, A Parthasarathy, R Aita, R Malhotra, J Hur, NH Toke, E Chiles, M Yang, W Cao, J Flores, CE Ellison, N Gao, A Sahota, X Su, EM Bonder, MP Verzi |
Nature Communications | 2021 |
|
Spatial transcriptional mapping of the human nephrogenic program
NO Lindström, R Sealfon, , RK Parvez, A Ransick, GD Brandine, J Guo, B Hill, T Tran, AD Kim, J Zhou, A Tadych, A Watters, A Wong, E Lovero, BH Grubbs, ME Thornton, JA McMahon, AD Smith, SW Ruffins, C Armit, OG Troyanskaya, AP McMahon |
Developmental Cell | 2021 |
|
Analysis of the HNF4A isoform-regulated transcriptome identifies CCL15 as a downstream target in gastric carcinogenesis
Z Ni, W Lu, Q Li, C Han, T Yuan, N Sun, Y Shi |
Cancer biology & medicine | 2021 |
|
The transcription factor HNF-4α: a key player in haematological disorders
Belali T, Abomughaid M, Alhujaily M |
Archives of Medical Science : AMS | 2021 |
|
Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury
J Wilflingseder, M Willi, HK Lee, H Olauson, J Jankowski, T Ichimura, R Erben, MT Valerius, L Hennighausen, JV Bonventre |
Nature Communications | 2020 |
|
Control of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology
V Dubois, B Staels, P Lefebvre, MP Verzi, J Eeckhoute |
Cells | 2020 |
|
A human cell atlas of fetal gene expression
J Cao, DR ODay, HA Pliner, PD Kingsley, M Deng, RM Daza, MA Zager, KA Aldinger, R Blecher-Gonen, F Zhang, M Spielmann, J Palis, D Doherty, FJ Steemers, IA Glass, C Trapnell, J Shendure |
Science | 2020 |
|
Hnf4a Is Required for the Development of Cdh6-Expressing Progenitors into Proximal Tubules in the Mouse Kidney
SS Marable, E Chung, JS Park |
Journal of the American Society of Nephrology : JASN | 2020 |
|
Molecular Basis for Autosomal-Dominant Renal Fanconi Syndrome Caused by HNF4A
V Marchesin, A Pérez-Martí, GL Meur, R Pichler, K Grand, ED Klootwijk, A Kesselheim, R Kleta, S Lienkamp, M Simons |
Cell Reports | 2019 |
|
β-catenin regulates the formation of multiple nephron segments in the mouse kidney
Patrick, CW Concodora, E Chung, JS Park |
Scientific Reports | 2019 |
|
Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
A Tin, J Marten, VL Kuhns, Y Li, M Wuttke, H Kirsten, KB Sieber, C Qiu, M Gorski, Z Yu, A Giri, G Sveinbjornsson, M Li, AY Chu, A Hoppmann, LJ OConnor, B Prins, T Nutile, D Noce, M Akiyama, M Cocca, S Ghasemi, PJ van der Most, K Horn, Y Xu, C Fuchsberger, S Sedaghat, S Afaq, N Amin, J Ärnlöv, SJ Bakker, N Bansal, D Baptista, S Bergmann, ML Biggs, G Biino, E Boerwinkle, EP Bottinger, TS Boutin, M Brumat, R Burkhardt, E Campana, A Campbell, H Campbell, RJ Carroll, E Catamo, JC Chambers, M Ciullo, MP Concas, J Coresh, T Corre, D Cusi, SC Felicita, MH de Borst, AD Grandi, R de Mutsert, AP de Vries, G Delgado, A Demirkan, O Devuyst, K Dittrich, KU Eckardt, G Ehret, K Endlich, MK Evans, RT Gansevoort, P Gasparini, V Giedraitis, C Gieger, G Girotto, M Gögele, SD Gordon, DF Gudbjartsson, V Gudnason, T Haller, P Hamet, TB Harris, C Hayward, AA Hicks, E Hofer, H Holm, W Huang, N Hutri-Kähönen, SJ Hwang, MA Ikram, RM Lewis, E Ingelsson, J Jakobsdottir, I Jonsdottir, H Jonsson, PK Joshi, NS Josyula, B Jung, M Kähönen, Y Kamatani, M Kanai, SM Kerr, W Kiess, ME Kleber, W Koenig, JS Kooner, A Körner, P Kovacs, BK Krämer, F Kronenberg, M Kubo, B Kühnel, ML Bianca, LA Lange, B Lehne, T Lehtimäki, J Liu, M Loeffler, RJ Loos, LP Lyytikäinen, R Magi, A Mahajan, NG Martin, W März, D Mascalzoni, K Matsuda, C Meisinger, T Meitinger, A Metspalu, Y Milaneschi, CJ ODonnell, OD Wilson, JM Gaziano, PP Mishra, KL Mohlke, N Mononen, GW Montgomery, DO Mook-Kanamori, M Müller-Nurasyid, GN Nadkarni, MA Nalls, M Nauck, K Nikus, B Ning, IM Nolte, R Noordam, JR OConnell, I Olafsson, S Padmanabhan, BW Penninx, T Perls, A Peters, M Pirastu, N Pirastu, G Pistis, O Polasek, B Ponte, DJ Porteous, T Poulain, MH Preuss, TJ Rabelink, LM Raffield, OT Raitakari, R Rettig, M Rheinberger, KM Rice, F Rizzi, A Robino, I Rudan, A Krajcoviechova, R Cifkova, R Rueedi, D Ruggiero, KA Ryan, Y Saba, E Salvi, H Schmidt, R Schmidt, CM Shaffer, AV Smith, BH Smith, CN Spracklen, K Strauch, M Stumvoll, P Sulem, SM Tajuddin, A Teren, J Thiery, CH Thio, U Thorsteinsdottir, D Toniolo, A Tönjes, J Tremblay, AG Uitterlinden, S Vaccargiu, P van der Harst, CM van Duijn, N Verweij, U Völker, P Vollenweider, G Waeber, M Waldenberger, JB Whitfield, SH Wild, JF Wilson, Q Yang, W Zhang, AB Zonderman, M Bochud, JG Wilson, SA Pendergrass, K Ho, A Parsa, PP Pramstaller, BM Psaty, CA Böger, H Snieder, AS Butterworth, Y Okada, TL Edwards, K Stefansson, K Susztak, M Scholz, IM Heid, AM Hung, A Teumer, C Pattaro, OM Woodward, V Vitart, A Köttgen |
Nature Genetics | 2019 |
