Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney disorders with a reported incidence ranging from 1:500 to 1:1000. The genes implicated in the disorder are PKD1 (encoding polycystin 1) and PKD2 (encoding polycystin 2) for ADPKD1 and ADPKD2 respectively.
Up to 10% patients may not have these well-described mutations, but may harbour a mutation in DNAJB11 or in one of the six mutations known to cause autosomal dominant polycystic liver disease(ADPLD) namely, AGL8, SEC61B, SEC63, PRKCSH, LRP5, and especially GANAB).
Even though the disorder is inherited in an autosomal dominant manner, it is to be emphasized that a single mutated gene may not be sufficient for cystogenesis. Rather, the cellular defect is most likely recessive because it is not without a second hit that the tubules produce a cyst. Additionally, though all the tubular cells carry at least one allele of the gene mutation, only a few of them develop cysts (about 1-3%).
Fundamentally, a cyst is a membranous sac – so it has two components- an epithelial lining and the fluid within. For the formation of a cyst, the intracellular pathways need to converge and promote two processes – epithelial proliferation and fluid secretion.
In ADPKD, the common link is cyclic adenosine monophosphate (cAMP). The enzyme adenylyl cyclase catalyzes the cyclisation of adenosine triphosphate (ATP) into cAMP, while another enzyme, phosphodiesterase breaks down the phosphodiester bond in the cAMP and degrades it (See Figure 1). Any event which either stimulates adenylyl cyclase or inhibits phosphodiesterase can lead to an increase in the intracellular levels of cAMP.
Though the exact mechanism leading to increased cAMP levels is unknown, it has been attributed to increased levels of circulating vasopressin. This may occur in response to loss of urinary concentrating ability seen quite early in the disease process.
While the cysts can arise from all nephron segments in ADPKD (including the glomerulus), microdissection studies done by O.Heggo revealed that the cysts derived from collecting ducts tend to be more numerous and larger.
Supporting this observation, the epithelium of the cysts was demonstrated to stain positive with lectins specific to the collecting duct. Vasopressin receptor 2 (V2R) is an abundantly expressed receptor in this part of the glomerulus. Binding of vasopressin to V2R stimulates adenylyl cyclase and inhibits phosphodiesterase as well leading to elevation of intracellular cAMP (see figure 2).
Recently, Su et al described the near-atomic resolution cryo-electron microscopic structure of PC1-PC2 complex in health and in ADPKD-1. The complex of polycystin-1 and polycystin-2 acts either as a mechanosensor or a chemosensor which normally translates the extracellular signals into intracellular increase in calcium.
This is mediated by two pathways – Ca2+ entry into the cells through PC2 and by release of Ca2+ from intracellular stores like endoplasmic reticulum (again mediated by PC2 and also ryanodine receptor). In ADPKD, as a result of the mutation in the genes encoding the aforementioned proteins, intracellular calcium levels are decreased. Please go through NephJC summary (and a video too) of this paper.
In normal kidney epithelial cells, cAMP inhibits proliferation of cells by inhibition of Raf-1/MAP kinase/extracellular signal regulated kinase (B-Raf-1/MEK/ERK), which is basically a pathway mediating cell proliferation. The tricky part here is that B-Raf can independently stimulate MAPK kinase and promote proliferation, but this is kept under check by Akt – which in turn requires normal intracellular Ca2+ levels to act.
When the intracellular Ca2+ levels go down (as happens in ADPKD), Akt is unable to inhibit the kinases and cell proliferation takes off unchecked. See the figure 3 below, from a nice review paper, which explains this schematically.
Also, Bhunia et al demonstrated that expression of PC1 in conjunction with PC2 activates JAK-STAT pathway, thereby upregulating p21.
p21 is essentially a guardian of the cell genome mediating inhibition of cell cycle (and even DNA repair). A defective PC1 or PC2 function, therefore, may hinder this process leading to uninhibited cell multiplication.
Intracellular cAMP levels may also be affected by somatostatin. Receptors for somatostatin, namely SSTR1 and 2 are expressed in the thick ascending limb of Henle, distal tubule and collecting duct and SSTR 3 and 4 are found in proximal tubules. Binding of somatostatin to its receptors inhibits the activity of adenylyl cyclase thereby reducing cAMP levels. Hence the interest in somatostatin analogues in inhibiting cyst growth, though the effect on kidney function was disappointing in the recent trial.
The C-terminal PC1 also has been demonstrated to interact with tuberin encoded by TSC2. By the virtue of this interaction, it inactivates the mTOR, which would otherwise promote cell growth, proliferation and this is the basis for the trials using mTOR inhibitors (sirolimus and everolimus) in ADPKD. The polycystin-tuberin interaction also explains the occurrence of renal cysts in tuberous sclerosis. Since the two genes PKD1 and TSC2 are located close to each other on chromosome 16p13, large deletions may involve both of them – the disease has been termed TSC2/PKD1 contiguous gene syndrome and is characterised by presence of renal cysts as well as angiomyolipomas.
Like probably all the renal epithelial cells, the basolateral surface of cyst epithelia also express Na+-K+-ATPase which functions to extrude sodium out of the cell in exchange for uptake of potassium. Sodium re-enters the cell via basolateral NKCC1 (sodium-potassium-chloride cotransporter), which also brings potassium as well as chloride into the cells. While potassium is returned extracellularly either by basolateral or apical potassium channels, chloride is transported into the cyst lumen principally along the electrochemical gradient via CFTR channel.
The activity of CFTR channel is upregulated in the setting of elevated intracellular cAMP levels. Cl secretion is accompanied by movement of Na and water into the cyst lumen. It is interesting to note that the patients who have the misfortune of having both PKD and cystic fibrosis have slower progression of cystic disease probably mediated by slower cyst growth due to impaired activity of CFTR. The same hypothesis has provided a foundation for pre-clinical trials for the role of CFTR inhibitors in animal models of ADPKD.
The diagram below summarises all the known pathways till date.
Nephrology Fellow, New Delhi
NSMC Intern, class of 2019
Nice diagramatic representation .
Excellent information and pictorial description of pathways leading to cystogenesis in ADPKD patients!!!