Hnf-1β Transcription Factor Is an Early Hif-1α-Independent Marker of Epithelial Hypoxia and Controls Renal Repair

Faguer, Stanislas; Mayeur, Nicolas; Casemayou, Audrey; Pageaud, Anne-Laure; Courtellemont, Claire; Cartery, C.; Fournié, Gilbert J.; Schanstra, Joost P.; Tack, Ivan; Bascands, Jean-Loup; Chauveau, Dominique

doi:10.1371/journal.pone.0063585

Cited by 23 publications

(18 citation statements)

References 35 publications

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“…Mutation or defects in HNF-1␤ lead to various renal diseases including cystic kidneys (41). HNF-1␤ has also been reported to associate with renal epithelial cell survival that may drive recovery and repair of kidney from ischemic injury (42). Our current study has demonstrated the first evidence for a protective role of HNF-1␤ in cisplatin nephrotoxicity.…”

Section: Discussionmentioning

confidence: 52%

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Hao

Lou

Wei

et al. 2017

Journal of Biological Chemistry

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Edited by Joel GottesfeldNephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatininduced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatininduced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One upregulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-B attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-B in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1␤) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1␤ protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-B collaboratively induce miR-375 expression, which, in turn, represses HNF-1␤ activity, resulting in renal tubular cell apoptosis and nephrotoxicity.

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Section: Discussionmentioning

confidence: 52%

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Hao

Lou

Wei

et al. 2017

Journal of Biological Chemistry

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“…43 In addition, during AKI, HNF-1b regulated the expression of genes important for homeostasis control, repair, and the state of epithelial cell differentiation. 44 A shortcoming of our study is the fact that we could not obtain detailed data on the probable cause of CKD for all patients (we obtained the probable cause of CKD for 91.4% of the patients) and that we lacked information on comorbidities. Therefore, there may be a potential selection bias or unknown (comorbidity) confounder effect.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

Schanstra

Zürbig

Alkhalaf

et al. 2015

Journal of the American Society of Nephrology

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212

197

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Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303620.065; P,0.001) and integrated discrimination improvement (0.05860.014; P,0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

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“…80,81 Hnf1b directly regulates the expression of Pkhd1 in tubular epithelial cells that are involved in tubulogenesis in the kidney, 82,83 and Socs3 which is essential for renal repair. 84 Although Hnf1a is expressed in the developing kidney and plays a role in kidney development, it is also a key regulator of numerous essential metabolic processes during adulthood. These include maintaining glucose homeostasis through regulation of the glucose-6-phosphatase system and the glucose transporter, as well as regulating other transporters that impact on the metabolism of amino acids because of impaired renal reabsorption.…”

Section: Key Pointmentioning

confidence: 99%

The molecular functions of hepatocyte nuclear factors – In and beyond the liver

Lau

Loo

et al. 2018

Journal of Hepatology

199

191

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The hepatocyte nuclear factors (HNFs) namely HNF1α/β, FOXA1/2/3, HNF4α/γ and ONECUT1/2 are expressed in a variety of tissues and organs, including the liver, pancreas and kidney. The spatial and temporal manner of HNF expression regulates embryonic development and subsequently the development of multiple tissues during adulthood. Though the HNFs were initially identified individually based on their roles in the liver, numerous studies have now revealed that the HNFs cross-regulate one another and exhibit synergistic relationships in the regulation of tissue development and function. The complex HNF transcriptional regulatory networks have largely been elucidated in rodent models, but less so in human biological systems. Several heterozygous mutations in these HNFs were found to cause diseases in humans but not in rodents, suggesting clear species-specific differences in mutational mechanisms that remain to be uncovered. In this review, we compare and contrast the expression patterns of the HNFs, the HNF cross-regulatory networks and how these liver-enriched transcription factors serve multiple functions in the liver and beyond, extending our focus to the pancreas and kidney. We also summarise the insights gained from both human and rodent studies of mutations in several HNFs that are known to lead to different disease conditions.

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Hnf-1β Transcription Factor Is an Early Hif-1α-Independent Marker of Epithelial Hypoxia and Controls Renal Repair

Cited by 23 publications

References 35 publications

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

The molecular functions of hepatocyte nuclear factors – In and beyond the liver

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