Both proteins are components of a receptor-channel complex that responds to local second messenger signals ( Harris and Torres, 2014). Disease causing mutations in the ciliary transmembrane proteins polycystin 1 ( PKD1) and polycystin 2 ( PKD2) underlie ADPKD ( Hughes et al., 1995 Mochizuki et al., 1996). In the kidney, primary cilia respond to fluctuations in fluid-flow through collecting ducts. They convert mechanical stimuli into biochemical signals to elicit developmental and regulatory responses ( Mukhopadhyay et al., 2013 Somatilaka et al., 2020). The primary cilium is a microtubule-based organelle protruding from the surface of most mammalian cells ( Satir et al., 2010). Hence this chronic renal disorder is classified as a ciliopathy ( Badano et al., 2006 Fliegauf et al., 2007). Clinical evidence indicates that primary cilia function is altered in ADPKD ( Ma et al., 2013 Ma et al., 2017). Autosomal dominant polycystic kidney disease (ADPKD) with an estimated prevalence of 1 in 600 people, is a common genetic disorder associated with end-stage renal failure ( Halvorson et al., 2010). Polycystic kidney diseases are disorders where the collecting ducts become enlarged with fluid filled cysts that reduce glomerular filtration rate ( Wilson, 2004). Approximately 35 million Americans suffer from chronic kidney diseases, characterized as a gradual loss of renal function ( Hemmelgarn et al., 2006). Not surprisingly, defects in renal water homeostasis have pathophysiological consequences. Water reabsorption from luminal fluid is triggered by the hormone arginine vasopressin via phosphorylation-dependent translocation of aquaporin-2 water pores to the apical surface of kidney collecting ducts ( Bankir et al., 2013 Noda et al., 2010 Yui et al., 2012). Kidneys recycle about 180 liters of fluid every day to partition nutrients and remove toxins from blood ( Saborio et al., 2000). These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. Pathophysiological defects in water homeostasis can lead to renal failure.
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