Physiologic mechanisms underlying polycystic kidney disease

Abstract

Polycystic kidney disease (PKD) encompasses a class of disorders presenting with bilateral cyst formation in the kidney. PKD can be inherited as a dominant (ADPKD) or a recessive (ARPKD) trait, due to mutations into multiple genes, the most frequent being PKD1, PKD2, and PKHD1. The protein products of these genes (polycystin-1, polycystin-2, and fibrocystin, respectively) have been shown to reside within the primary cilium or to be important for the maturation and trafficking of proteins to the primary cilium. The primary cilium is an organelle protruding from the apical surfaces of renal epithelial cells that functions to sense extracellular signals and translate them into intracellular biochemical information. PKD represents the most common monogenic disorder affecting the kidney and the most common manifestation of human ciliopathies. The precise functions of the polycystin and fibrocystin proteins have not yet been fully elucidated nor have the molecular basis underlying the renal tubule cyst formation that occurs in the absence of sufficient functional expression of these proteins. The genes that are muted in PKD were cloned three decades ago, and since their identification, a wealth of information regarding their structure, cell biology, and physiological properties has been developed. Here, we provide a broad review of the relevant literature and summarize a large body of experimental evidence, while focusing particularly on more recent findings that are poised to change our understanding of the field.

Keywords: cyst; kidney; polycystic kidney disease; polycystin; signaling.

Figure 1:

A. Schematic representation of the focal manifestations of cysts in all nephron segments in ADPKD; B. Schematic representation of the fusiform dilatations of the collecting ducts typical of ARPKD.

Figure 2:

A. Schematic representation of the Polycystin-1 (PC-1) and Polycystin-2 (PC-2) proteins and their structural domains. LRR, leucine rich repeats; PKD, PKD repeats; FNIII, fibronectin II like domains; GPS, G-protein coupled receptor proteolytic site; TOP, tetragonal opening for polycystins domain. B. Structure of the full-length Polycystin-1 protein and its reported cleavage sites.

Figure 3:

CryoEM structure of the PC-1/PC-2 complex as published in Su et al., Science 2018.

Figure 4:

Cartoon depicting the subcellular sites at which the polycystin proteins are thought to function, including the cilium and Mitochondria-ER contact sites. The diagram also depicts the resident ER proteins that are thought to be involved in the folding and assembly of the newly synthesized polycystin proteins, and whose genetic absence can lead to cystic disease.

Figure 5:

Cartoon representing the role that the Cilia Dependent Cyst Activating (CDCA) pathway has been suggested to play in PKD. In wild type kidneys the ciliary PC-1/PC-2 complex inhibits a cilia-driven pathway that would otherwise be constitutively active and cause cyst formation. Removal of cilia results in a reduced inhibitory activity by the polycystins, causing a mild cystic disease. Removal of the polycystins in the presence of normal cilia results in a very aggressive PKD phenotype. In this context, removing cilia partially ameliorates the phenotype.

Figure 6:

Structure of PC-1 c-terminal tail. In brown is indicated the coiled-coil (CC) domain, in light blue the mitochondrial targeting sequence (MTS), nuclear localization signal (NLS), Gα binding site (Gα ). The caspase cleavage site and the active polyproline motif are also indicated.

Figure 7:

Schematic representation of the homotetrameric Polycystin-2 channel (left) or heterotetrameric Polycystin-1/Polycystin-2 channel (right) and their reported preferences for monovalent or divalent cations, respectively.

Figure 8:

Overview of selected signaling pathways that are altered in ADPKD cystic epithelia. The polycystins proteins are found in the cilium, the ER and the MERCs. Pathways depicted in green are thought to be downregulated in PKD cyst cells, while those depicted in in violet are thought to be upregulated in PKD.

Figure 9:

Both healthy and cystic epithelia are fully polarized, with the Na,K-ATPase pump properly located on the basolateral side. Normal absorptive renal epithelial cells exploit the gradient created by the Na,K-ATPase to drive the apical to basolateral transport of sodium and chloride ions. In the case of cells of the thick ascending limb (right panel), this is accomplished via an apical Na,K,2CL cotransporter (NKCC2) and basolateral chloride and potassium channels. Cystic Epithelia (left panel) secrete fluid and electrolytes by virtue of apical expression of the CFTR chloride transporter in concert with the basolateral NKCC1 isoform of the Na,K,2Cl cotransporter.

Figure 10:

Overview of the metabolic reprogramming that occurs in PKD. Enhanced glycolysis and reduced Oxidative phosphorylation are observed. A compensatory increased glutaminolysis, which drives reductive carboxylation, enhances citrate export from mitochondria to drive fatty acid biosynthesis. The increased uptake of glucose fuels the pentose phosphate pathway (PPP) which generates reductive power in the form of NADPH to drive fatty acid biosynthesis. The accumulation of Malonyl-CoA blocks the carnitine transporters CPT1 and CPT2, causing reduced beta-oxidation.