Fluid transport and cystogenesis in autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy. The development and enlargement of cysts in ADPKD requires tubular cell proliferation, abnormalities in the extracellular matrix and transepithelial fluid secretion. Multiple studies have suggested that fluid secretion across ADPKD cyst-lining cells is driven by the transepithelial secretion of chloride, mediated by the apical CFTR channel and specific basolateral transporters. The whole secretory process is stimulated by increased levels of cAMP in the cells, probably reflecting modifications in the intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor. This review will focus on the pathophysiology of fluid secretion in ADPKD cysts, starting with classic, morphological and physiological studies that were followed by investigations of the molecular mechanisms involved and therapeutic trials targeting these pathways in cellular and animal models and ADPKD patients. This article is part of a Special Issue entitled: Polycystic Kidney Disease.

Vasopressin-2 Receptor Signaling and Autosomal Dominant Polycystic Kidney Disease

“…34 The decreased activity of MAPKs after physiologic vasopressin stimulation is also associated with decreased phosphorylation and activity of known MAPKdependent transcription factors, including activating transcription factor 2 and the tumor suppressor protein p53. 36 In addition, nuclear abundance of JunD is significantly decreased in response to dDAVP. 56 Also, phosphorylation of c-Jun in the nucleus is decreased in response to dDAVP.…”

“…39 The pathophysiology of regulation of secretion of fluids and electrolytes into the cyst lumen has been reviewed in detail elsewhere. 36 However, cAMP-dependent regulation of transport activity of other segments of the nephron, such as the mTAL of the Henle loop, are not well studied in ADPKD, although mTAL is volumetrically the predominant structure in the outer medulla. [40][41][42] V2R activation may lead to a significant increase in activity or abundance of the active sodium transporters, the apical membrane type 3 Na + /H + exchanger and Na + :K + :2Cl 2 cotransporter cotransporter in vivo.…”

“…Phosphorylation at S16 of stathmin is increased by V2R activation. 36 Interestingly, this protein is involved in microtubule stabilization, 48,49 and phosphorylation at S16 can only be observed during formation of the mitotic spindle. 48 However, the role of V2R activation in microtubule control is still elusive, although some initial studies have been performed in cultured cells.…”

“…However, until recently, the role of V2R signaling in MAPK activation remained elusive, which changed with a recent systems biology study using highthroughput quantitative phosphoproteomic analyses after V2R activation in mpkCCD cells. 36 V2R stimulation causes a decrease of the activity of various MAPKs, at least under physiologic conditions. Quantitative global phosphoproteomic analyses using both native tissue, as well as mpkCCD cells, revealed that treatment with a V2R agonist caused a significant decrease in phosphorylation of proline-directed phosphorylation motifs, thereby suggesting inhibited activity of MAPKs.…”

“…36 Interestingly, cyst secretion preferably occurs in conjunction with nucleotides, such as ATP. 37 Elegant studies showed that these nucleotides are released in response to physiologic concentrations of AVP in the cortical and inner medullary collecting ducts at very high local concentrations of up to 0.3 mM.…”