| First Author | Buchholz B | Year | 2014 |
| Journal | J Am Soc Nephrol | Volume | 25 |
| Issue | 3 | Pages | 465-74 |
| PubMed ID | 24203996 | Mgi Jnum | J:320189 |
| Mgi Id | MGI:6868399 | Doi | 10.1681/ASN.2013030209 |
| Citation | Buchholz B, et al. (2014) Hypoxia-inducible factor-1alpha causes renal cyst expansion through calcium-activated chloride secretion. J Am Soc Nephrol 25(3):465-74 |
| abstractText | Polycystic kidney diseases are characterized by numerous bilateral renal cysts that continuously enlarge and, through compression of intact nephrons, lead to a decline in kidney function over time. We previously showed that cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1alpha (HIF-1alpha) in the cyst epithelium. Here we demonstrate a correlation between cyst size and the expression of the HIF-1alpha-target gene, glucose transporter 1, and report that HIF-1alpha promotes renal cyst growth in two in vitro cyst models-principal-like MDCK cells (plMDCKs) within a collagen matrix and cultured embryonic mouse kidneys stimulated with forskolin. In both models, augmenting HIF-1alpha levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate enhanced cyst growth. In addition, inhibition of HIF-1alpha degradation through tubule-specific knockdown of the von Hippel-Lindau tumor suppressor increased cyst size in the embryonic kidney cyst model. In contrast, inhibition of HIF-1alpha by chetomin and knockdown of HIF-1alpha both decreased cyst growth in these models. Consistent with previous reports, plMDCK cyst enlargement was driven largely by transepithelial chloride secretion, which consists, in part, of a calcium-activated chloride conductance. plMDCKs deficient for HIF-1alpha almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal cysts contributes to cyst growth, primarily due to HIF-1alpha-dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of cyst growth. |
