SERCA Enzymes as Targets for Polycystic Kidney Disease
SERCA enzymes have emerged as potential therapeutic targets for Polycystic Kidney Disease (PKD), a prevalent hereditary kidney disease estimated to affect over 12 million people worldwide.
Polycystic Kidney Disease (PKD)
Polycystic Kidney Disease (PKD) is a hereditary disorder estimated to affect over 12 million people worldwide.¹ PKD is characterized by fluid-filled cysts predominantly in the kidneys, which leads to enlargement and damage to organs.
There are two main types of PKD: Autosomal Dominant (ADPKD) and Autosomal Recessive (ARPKD), distinguished primarily by their onset. ADPKD develops during adulthood, while ARPKD manifests during fetal development or early childhood. ARPKD is relatively rare, affecting 1 in 20,000 live births.² Whereas, ADPKD is more prevalent and is the most frequent genetic cause of kidney failure.³
Lack of a Cure for ADPKD
ADPKD presents significant challenges due to progressive kidney damage and systemic manifestations, leading to complications such as kidney stones and UTIs. Current management strategies focus on alleviating symptoms and slowing kidney decline. This can include blood pressure control, pain management, peritoneal dialysis or kidney transplantation.
Genetic testing can help in diagnosing ADPKD and identifying individuals at risk with a family history of the disease. Recent advancements have shown progress in delaying ADPKD with the use of medications including tolvaptan, rapamycin, and somatostatin.⁴ Despite these advancements, there is no cure for ADPKD and finding a lasting solution remains critical.
Uncovering Targets for ADPKD
Causaly’s machine learning technology has extensively analyzed the literature, revealing a comprehensive list over 300 targets associated with ADPKD. In this use case, we have refined targets of ADPKD by in vitro studies, uncovering around 20 targets. Targets of interest were selected by the amount of evidence, in addition to the strength of evidence.
Most evidence: PKD1 gene
The PKD1 gene stands out as having the most substantial evidence as a target ADPKD. Research has shown that genetic mutations in PKD1 play a crucial role in predicting renal dysfunction in ADPKD patients. One study with Japanese patients with ADPKD found that those with PKD1 mutations showed a more significant decline in kidney function compared to those with PKD2 mutations.⁵ Another study identified biallelic PKD1 variants in early-onset ADPKD cases, revealing the genetic mechanism behind severe presentations.⁶ These findings suggest that PKD1 could be a promising target for treatment of ADPKD.
Emerging Targets: SERCA Enzymes
One of the most recently reported targets was a Sarcoplasmic Reticulum Calcium-Transporting ATPase (SERCA). SERCA enzymes are crucial for maintaining intracellular calcium homeostasis, which is important for biological functions including cell signaling and contraction.
Research has demonstrated that inhibiting SERCA activity can hinder ADPKD cell proliferation by promoting autophagy.⁷ In vitro and in vivo studies supported these findings, suggesting that the degradation of SERCA2 is involved in Ca2+ imbalance, leading to kidney cell death.⁸ Additionally, inhibition of SERCA expression with cadmium disrupted Ca2+ homeostasis and induced apoptosis in kidney cells.⁸
ADPKD is a challenging hereditary kidney disease with no cure, necessitating continuous research to identify effective therapeutic targets. SERCAs emerge as promising targets for ADPKD due to their role in calcium homeostasis and cyst growth regulation. In ADPKD, the disruption to calcium signaling contributes to cyst growth and disease progression. Therefore, modulating SERCA activity may offer a unique treatment strategy to slow ADPKD and relieve symptoms.
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