| First Author | Aboudehen K | Year | 2017 |
| Journal | J Am Soc Nephrol | Volume | 28 |
| Issue | 10 | Pages | 2887-2900 |
| PubMed ID | 28507058 | Mgi Jnum | J:290181 |
| Mgi Id | MGI:6437652 | Doi | 10.1681/ASN.2016101095 |
| Citation | Aboudehen K, et al. (2017) Hepatocyte Nuclear Factor-1beta Regulates Urinary Concentration and Response to Hypertonicity. J Am Soc Nephrol 28(10):2887-2900 |
| abstractText | The transcription factor hepatocyte nuclear factor-1beta (HNF-1beta) is essential for normal kidney development and function. Inactivation of HNF-1beta in mouse kidney tubules leads to early-onset cyst formation and postnatal lethality. Here, we used Pkhd1/Cre mice to delete HNF-1beta specifically in renal collecting ducts (CDs). CD-specific HNF-1beta mutant mice survived long term and developed slowly progressive cystic kidney disease, renal fibrosis, and hydronephrosis. Compared with wild-type littermates, HNF-1beta mutant mice exhibited polyuria and polydipsia. Before the development of significant renal structural abnormalities, mutant mice exhibited low urine osmolality at baseline and after water restriction and administration of desmopressin. However, mutant and wild-type mice had similar plasma vasopressin and solute excretion levels. HNF-1beta mutant kidneys showed increased expression of aquaporin-2 mRNA but mislocalized expression of aquaporin-2 protein in the cytoplasm of CD cells. Mutant kidneys also had decreased expression of the UT-A urea transporter and collectrin, which is involved in apical membrane vesicle trafficking. Treatment of HNF-1beta mutant mIMCD3 cells with hypertonic NaCl inhibited the induction of osmoregulated genes, including Nr1h4, which encodes the transcription factor FXR that is required for maximal urinary concentration. Chromatin immunoprecipitation and sequencing experiments revealed HNF-1beta binding to the Nr1h4 promoter in wild-type kidneys, and immunoblot analysis revealed downregulated expression of FXR in HNF-1beta mutant kidneys. These findings reveal a novel role of HNF-1beta in osmoregulation and identify multiple mechanisms, whereby mutations of HNF-1beta produce defects in urinary concentration. |
