Challenges for current thinking about autosomal dominant polycystic kidney disease

Recent research published in JASN uncovers an over-looked mechanism that likely contributes to this condition. The findings provide a better understanding of ADPKD and may lead to new strategies to treat it. Research indicates that the polycystin-2 protein in cells' endoplasmic reticulum is important for maintaining kidney health, and its lack can contribute to autosomal dominant polycystic kidney disease.

Loss of PC1 and PC2 in cilia is believed central to the pathogenesis of cyst formation that's a hallmark of Autosomal dominant polycystic kidney disease. PC1 and PC2 can be expressed in other locations, however, and it's unclear if these forms of the proteins are also important for preventing Autosomal dominant polycystic kidney disease.

To investigate, researchers examined the role of PC2 in the endoplasmic reticulum (ER), a structure within cells that's involved in protein and lipid synthesis. The team found that PC2 in the ER is important for maintaining kidney health and that its loss can lead to cyst formation.

Endoplasmic reticulum -localized PC2 blocks cysts presumably by functioning as a potassium channel to facilitate the exchange of potassium and calcium. When the researchers bred mice to lack PC2, the animals developed cysts, but this could be reversed by breeding the PC2-lacking mice to express a different potassium channel called TricB in the endoplasmic reticulum.

"Current dogma of ADPKD is that it is a disease in which defects primarily originate in the cilia. We demonstrate that defects in the ER perhaps play a more important role, furthermore, the function of PC2 in the endoplasmic reticulum is to regulate potassium movement to affect calcium balance indirectly. In addition to providing these insights, the research suggests that activating TricB may be a promising treatment strategy for Autosomal dominant polycystic kidney disease.

Reference: "Study results challenge current thinking about autosomal dominant polycystic kidney disease"; AMERICAN SOCIETY OF NEPHROLOGY, Journal of the American Society of Nephrology DOI:10.1681/ASN.2022010053.