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.
Highlights
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is among the most commonly inherited, life-threatening diseases, affecting 1:500 adults worldwide
We found increased GLI1 in ADPKD compared to normal human kidney (NHK) tissue (Fig. 1A; Figures S1; S2)
While cystic cells did not label with Lotus tetragonolobulus (LTL), a marker of proximal tubules, Dolichos biflorus agglutinin (DBA) or Tamm-Horsfall Protein (THP) staining of cystic cells suggested that the cysts originated from collecting duct or Loop of Henle tubules, respectively, and that GLI1-positive epithelial cells were present in these cysts (Fig. 2; Figure S4)
Summary
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is among the most commonly inherited, life-threatening diseases, affecting 1:500 adults worldwide. ADPKD is characterized by the formation and growth of fluid-filled cysts in the kidneys, which compress neighboring tubules, resulting in renal injury and fibrosis Many of these patients progress to end stage renal disease (ESRD) by the 6th decade of life. Genetic ablation of primary cilia in Pkd[1] and Pkd[2] conditional knock-out mice attenuated PC-mediated renal cystogenesis, which led to the proposal that an undefined cilia-dependent signaling pathway promotes PC-deficient cyst formation[5]. Deletion of Ift-B or -A genes in the kidney or globally during late embryogenesis causes renal cysts[13,14,15]
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