Hypoxia-Inducible Factor-1α Causes Renal Cyst Expansion through Calcium-Activated Chloride Secretion

Abstract

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-1a (HIF-1a) in the cyst epithelium. Here we demonstrate a correlation between cyst size and the expression of the HIF-1a-target gene, glucose transporter 1, and report that HIF-1a 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-1a levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate enhanced cyst growth. In addition, inhibition of HIF-1a 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-1a by chetomin and knockdown of HIF-1a 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-1a almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal cysts contributes to cyst growth, primarily due to HIF-1a-dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of cyst growth.

Combined Deletion of Vhl and Kif3a Accelerates Renal Cyst Formation

“…A more general role for HIF1a stabilization in cyst progression has been recently proposed. 19,20 However, in this study, we find that cystic lesions induced by Kif3a deletion are not characterized by HIF1a stabilization nor does the deletion of Hif1a have any effect on the formation of cysts in this model. HIF1a stabilization may be limited to more severe polycystic kidneys than achieved in this model, or cellular signaling changes induced by mutation of the PKD1/ PKD2 genes in autosomal dominant polycystic kidney disease may contribute to HIF1a activation in cysts through constitutive mammalian target of rapamycin activation, [35][36][37] which causes enhanced translation of HIF1a.…”

“…22 Cysts either do not receive the contrast agent or fail to concentrate it and therefore appear as dark regions in mCT imaging. Mice were imaged at 8,16,20,24,28,32, and 36 weeks after administration of tamoxifen food ( Figure 2). Kidneys were isolated and blood plasma was taken after the last time point.…”

“…19 Based on two in vitro models of cyst formation, it was proposed that Hif1a activation promotes cyst formation. 20 However, whether HIF1a contributes to the formation or progression of cystic lesions has not been tested in a physiologically relevant cystic model. We tested this idea by deleting Hif1a in the Kif3a-deletion model of kidney cyst formation.…”

Sleep-Disordered Breathing in Patients with Polycystic Liver and Kidney Disease Referred for Transcatheter Arterial Embolization

“…Recent research using animal models implicates hypoxia as a potentially important pathomechanism in the progression of ADPKD (15)(16)(17). Compromised blood flow and a mismatch between expanding cysts and the vascularization of cyst walls in ADPKD engender regional hypoxia and consecutive upregulation of HIF in the cyst epithelium.…”

“…The activation of the HIF pathway increases pericystic angiogenesis and the expression of several angiogenic factors such as erythropoietin (15,18). Furthermore, systemic and regional hypoxia engender the stabilization of HIF-1a in the cyst epithelium, and promote renal cyst growth attributable to HIF-1a-dependent calcium-activated chloride secretion in ADPKD (17,19). Intermittent hypoxia associated with SDB has also been shown to induce HIF-1a protein expression and transactivation in a ROS-dependent manner (20).…”