Inhibition of Hedgehog signaling suppresses proliferation and microcyst formation of human Autosomal Dominant Polycystic Kidney Disease cells

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutation of PKD1 or PKD2, which encode polycystin 1 and 2, respectively. The polycystins localize to primary cilia and the functional loss of the polycystin complex leads to the formation and progressive growth of fluid-filled cysts in the kidney. The pathogenesis of ADPKD is complex and molecular mechanisms connecting ciliary dysfunction to renal cystogenesis are unclear. Primary cilia mediate Hedgehog signaling, which modulates cell proliferation and differentiation in a tissue-dependent manner. Previously, we showed that Hedgehog signaling was increased in cystic kidneys of several PKD mouse models and that Hedgehog inhibition prevented cyst formation in embryonic PKD mouse kidneys treated with cAMP. Here, we show that in human ADPKD tissue, Hedgehog target and activator, Glioma 1, was elevated and localized to cyst-lining epithelial cells and to interstitial cells, suggesting increased autocrine and paracrine Hedgehog signaling in ADPKD, respectively. Further, Hedgehog inhibitors reduced basal and cAMP-induced proliferation of ADPKD cells and cyst formation in vitro. These data suggest that Hedgehog signaling is increased in human ADPKD and that suppression of Hedgehog signaling can counter cellular processes that promote cyst growth in vitro.

Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content

“…We also identified the ciliary protein ARL13b. This protein is involved in hedgehog signaling [27,28], which in turn appears to be involved in cystogenesis [29] and even malignancy [30].…”

Tulp3 Is a Ciliary Trafficking Gene that Regulates Polycystic Kidney Disease

“…In the mouse embryo, deletion of Tulp3 causes upregulation of the Sonic Hedgehog (Shh) pathway in the neural tube in a Gli-dependent manner and causes skeletal defects consistent with Shh pathway dysregulation [19][20][21][22]. In addition, it has been postulated that activation of the Shh pathway is associated with ADPKD [10,36]. However, Tulp3…”

Co-Inheritance of Autosomal Dominant Polycystic Kidney Disease and Naevoid Basal Cell Carcinoma Syndrome: Effects on Renal Progression

“…Accordingly, Song et al [9] reported an upregulation of some HH signalling components (i.e., PTCH1 and GLI2 mRNAs) in renal cysts from patients with PKD1, suggesting a modest role of the pathway in human cystogenesis. In a very recent work, Silva et al [33] elegantly show that although the transcription factor GLI1 increased in ADPKD primary renal epithelial cells compared to normal renal cells, no altered activation of the HH pathway in the cilia were found. Likewise, in vitro studies showed no difference between both types of cells in proliferation and microcyst development, even after treatment with cyclic AMP [33].…”

“…In a very recent work, Silva et al [33] elegantly show that although the transcription factor GLI1 increased in ADPKD primary renal epithelial cells compared to normal renal cells, no altered activation of the HH pathway in the cilia were found. Likewise, in vitro studies showed no difference between both types of cells in proliferation and microcyst development, even after treatment with cyclic AMP [33].…”