HNF-1B specifically regulates the transcription of the γa-subunit of the Na+/K+-ATPase

113

Nephrons comprise a blood filter and an epithelial tubule that is subdivided into proximal and distal segments, but what directs this patterning during kidney organogenesis is not well understood. Using zebrafish, we found that the HNF1b paralogues hnf1ba and hnf1bb, which encode homeodomain transcription factors, are essential for normal segmentation of nephrons. Embryos deficient in hnf1ba and hnf1bb did not express proximal and distal segment markers, yet still developed an epithelial tubule. Initiating hnf1ba/b expression required Pax2a and Pax8, but hnf1ba/b-deficient embryos did not exhibit the expected downregulation of pax2a and pax8 at later stages of development, suggesting complex regulatory loops involving these molecules. Embryos deficient in hnf1ba/b also did not express the irx3b transcription factor, which is responsible for differentiation of the first distal tubule segment. Reciprocally, embryos deficient in irx3b exhibited downregulation of hnf1ba/b transcripts in the distal early segment, suggesting a segment-specific regulatory circuit. Deficiency of hnf1ba/b also led to ectopic expansion of podocytes into the proximal tubule domain. Epistasis experiments showed that the formation of podocytes required wt1a, which encodes the Wilms' tumor suppressor-1 transcription factor, and rbpj, which encodes a mediator of canonical Notch signaling, downstream or parallel to hnf1ba/b. Taken together, these results suggest that Hnf1b factors are essential for normal segmentation of nephrons during kidney organogenesis.

Section: Discussionmentioning

confidence: 98%

HNF1β Is Essential for Nephron Segmentation during Nephrogenesis

Naylor

Przepiorski

Ren

et al. 2013

113

“…1,5 It was shown that HNF1B binds the FXYD2 promoter to specifically regulate the transcription of the g-subunit of the Na + /K + -ATPase isoforma. 1,6 ga-Subunit is mainly expressed in proximal tubule and medullary TAL, but it is also expressed in DCT (Supplemental Figure 3), 6,27 where PCBD1 is expressed. To date, the exact molecular mechanism by which the g-subunit regulates Mg 2+ handling in DCT remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…5 More recently, functional HNF1B binding sites were identified in the promoter region of FXYD2, suggesting that impaired transcription of FXYD2 by HNF1B results in renal Mg 2+ wasting. 1,6 Additional HNF1B target genes in kidney include renal cystic genes [7][8][9] as well as genes involved in tubular electrolyte transport. 10,11 HNF1B forms heterotetrameric complexes with the protein pterin-4a-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 homeobox A (PCBD1 [MIM 126090]).…”

mentioning

confidence: 99%

Mutations in PCBD1 Cause Hypomagnesemia and Renal Magnesium Wasting

Ferrè

Baaij

Ferreira

et al. 2014

Self Cite

Mutations in PCBD1 are causative for transient neonatal hyperphenylalaninemia and primapterinuria (HPABH4D). Until now, HPABH4D has been regarded as a transient and benign neonatal syndrome without complications in adulthood. In our study of three adult patients with homozygous mutations in the PCBD1 gene, two patients were diagnosed with hypomagnesemia and renal Mg 2+ loss, and two patients developed diabetes with characteristics of maturity onset diabetes of the young (MODY), regardless of serum Mg 2+ levels. Our results suggest that these clinical findings are related to the function of PCBD1 as a dimerization cofactor for the transcription factor HNF1B. Mutations in the HNF1B gene have been shown to cause renal malformations, hypomagnesemia, and MODY. Gene expression studies combined with immunohistochemical analysis in the kidney showed that Pcbd1 is expressed in the distal convoluted tubule (DCT), where Pcbd1 transcript levels are upregulated by a low Mg 2+ -containing diet. Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg 2+ reabsorption in the DCT. Of seven PCBD1 mutations previously reported in HPABH4D patients, five mutations caused proteolytic instability, leading to reduced FXYD2 promoter activity. Furthermore, cytosolic localization of PCBD1 increased when coexpressed with HNF1B mutants. Overall, our findings establish PCBD1 as a coactivator of the HNF1B-mediated transcription necessary for fine tuning FXYD2 transcription in the DCT and suggest that patients with HPABH4D should be monitored for previously unrecognized late complications, such as hypomagnesemia and MODY diabetes.

“…18 Ferrè et al confirmed that HNF1b specifically acts as an activator of the g-subunit and that HNF1B mutations identified in patients with hypomagnesemia prevented g-subunit transcriptional activation, with a dominant negative effect on wild-type HNF1b. 19 The combination of hypomagnesemia and hypocalciuria is also encountered in Gitelman syndrome, in which a defect of distal convoluted tubule sodium chloride cotransport is involved. Of note, in two of the above-described patients, the diagnosis of Gitelman syndrome was initially considered.…”

Section: Hypomagnesemia and Hypocalciuriamentioning

confidence: 99%

Hepatocyte Nuclear Factor 1β–Associated Kidney Disease

Verhave

Bech

Wetzels

et al. 2016

132

121

Hepatocyte nuclear factor 1b (HNF1b)-associated disease is a recently recognized clinical entity with a variable multisystem phenotype. Early reports described an association between HNF1B mutations and maturity-onset diabetes of the young. These patients often presented with renal cysts and renal function decline that preceded the diabetes, hence it was initially referred to as renal cysts and diabetes syndrome. However, it is now evident that many more symptoms occur, and diabetes and renal cysts are not always present. The multisystem phenotype is probably attributable to functional promiscuity of the HNF1b transcription factor, involved in the development of the kidney, urogenital tract, pancreas, liver, brain, and parathyroid gland. Nephrologists might diagnose HNF1b-associated kidney disease in patients referred with a suspected diagnosis of autosomal dominant polycystic kidney disease, medullary cystic kidney disease, diabetic nephropathy, or CKD of unknown cause. Associated renal or extrarenal symptoms should alert the nephrologist to HNF1b-associated kidney disease. A considerable proportion of these patients display hypomagnesemia, which sometimes mimics Gitelman syndrome. Other signs include early onset diabetes, gout and hyperparathyroidism, elevated liver enzymes, and congenital anomalies of the urogenital tract. Because many cases of this disease are probably undiagnosed, this review emphasizes the clinical manifestations of HNF1b-associated disease for the nephrologist.