Polycystic kidney disease (PKD) is a common genetic disorder that affects over 12 milion people globally (PKD International, 2019).

Multiple cysts develop along the kidney as round sacs filled with fluid. PKD is caused by mutations of two gene proteins, PKD1 and PKD2, and typically affects people in their adulthood. The kidney becomes larger, and possibly non-functional overtime.

Researchers in cell biology, the medical field, and the pharmaceutical industry entered a 125+ year journey in attempt to understand the mechanisms for proper treatment. This has occurred since Flix Lejars first described polycystic kidneys in 1888 (Balat et al, 2016). The cyst growth cannot be fully stopped and no cure exist yet, but various therapeutic options are arising. The most successful being the US FDA approved, Tolvaptran (PKD Cure, 2018).

Next advancements in therapeutic options lie in understanding the root mechanisms behind PKD. The mutation of PKD1 gene contributes to 85% of confirmed cases, and the PKD2 gene accounts for 15% of cases. They both serve different functions. Ultimately, they form a polycystin complex made of polycystin-1 (PC1) and polycystin-2 (PC2) in the primary cilia of epithelial cells. However, a big questions mark looms over exactly how they work. It is commonly thought that Polycystin-1(PC1) is a big membrane receptor protein that regulates ion channel complexes. In comparison, polycystin-2 (PC2) is a basic membrane protein that serves to channel calcium. It is thought that the imbalance between PC1 and PC2 causes disruption in normal signaling pathways that are leading to PKD (Mangolini et al, 2016). 

Recent research shows promise through visual analysis and inhibition of a key messenger molecule (Torres et al, 2019). We will take a closer look at the roles of calcium and cyclic adenosine monophosphate (cAMP) in recent research discoveries.

To further understand the assembly and function of PKD1 and PKD2, structural biology researchers at Tsinghua University’s School of Medicine investigated PC1 and PC2 complex through visual analysis. They used a PC1-PC2 complex that was purified from human embryonic kidney (HEK) 293F cells. They used an advanced cyro-electron microscopy technique with 3.6-angstrom resolution to find that the complex doesn’t actually form a permeable channel for calcium. This research suggests that PKD may not develop due to irregularity in the channel, but by errors in the
folding complex (Su et al, 2018). The visualization of the mechanism is a major accomplishment toward understanding PKD.

A key contributor to PKD is high levels of cyclic adenosine monophosphate (cAMP), a messenger molecule within cells. It is present in cyst epithelial cells, regulates the rate at which the cyst cells grow, and is responsible for the fluid production in the cysts (Belibi et al, 2004). In other words, cAMP tells cells when to divide and when to release fluid.

A recent development by biologists at Mironid Ltd and University of Sheffield has led to excitement over a new class of drugs to treat PKD by targeting cAMP. A small molecule was found to activate an enzyme, PDE4, which naturally helps degrade cAMP activity. Primary PKD human kidney cells were used in the study to confirm the mode of blocking molecular action (Bowers et al, 2019; University of Sheffield, 2019).

In another progressive study, cell biologists and kidney researchers at the University of Kansas Medical Center prevent hedgehog signaling using inhibitors as an approach to reduce cAMP activity and cyst growth. A mix of human PKD tissue, normal human kidney tissue, and primary cells were used during the in vitro studies. Specifically, the hedgehog signal, Glioma 1, was found at high levels in the cyst-lined epithelial cells (Silva et al, 2018). Hedgehog signaling assists in embryonic development and tissue homeostasis, but its irregular signals can trigger PKD as well as various types of cancers (Cell Signaling Technology, 2019).

The knowledge these researchers have contributed to the field and the high quality experiments with human cells pave a promising path toward viable treatment of this genetic disease.