Research findings point to new therapeutic approach for common cause of kidney failure

New research has uncovered a process that is defective in patients with autosomal dominant polycystic kidney disease, a common cause of kidney failure. The findings, which appear in an upcoming issue of the Journal of the American Society of Nephrology (JASN), point to a new potential strategy for preventing and treating the disease.

Polycystic (PKD), the fourth leading cause of kidney failure worldwide, comes in two forms: autosomal dominant (ADPKD) develops in adulthood and is quite common, while autosomal recessive polycystic kidney disease (ARPKD) is rare but frequently fatal. ADPKD is caused by in either of two proteins, polycystin-1 and polycystin-2, while ARPKD is caused by mutations in a protein called fibrocystin. There is no cure or widely adopted clinical therapy for either form of the disease.

Polycystin-1, polycystin-2, and fibrocystin are all found in a cell's primary cilium, which acts as the cell's antenna and is intimately involved in human embryonic development as well as the development of certain diseases, including PKD. "What we don't know, and were hoping to better understand, is what goes wrong with these proteins in the cells of PKD patients and what kinds of therapies might help those cells," said Joseph Bonventre, MD, PhD (Brigham and Women's Hospital).

Dr. Bonventre and his colleagues Benjamin Freedman, PhD and Albert Lam, MD led a team of scientists at Brigham and Women's Hospital, the Mayo Clinic, and the Harvard Stem Cell Institute as they studied cells obtained from five PKD patients: three with ADPKD and two with ARPKD. The investigators reprogrammed patients' into induced , which can give rise to many different cell types and tissues. When the researchers examined these cells under the , they discovered that the polycystin-2 protein traveled normally to the antenna, or cilium, in cells from ARPKD patients, but it had trouble reaching the antenna in ADPKD patients. When they sequenced the DNA in these ADPKD patient cells, the investigators found mutations in the gene that encodes polycystin-1, suggesting that polycystin-1 helps shepherd polycystin-2 to the cilium.

"When we added back a healthy form of polycystin-1 to our patient cells, it traveled to the and brought its partner polycystin-2 with it, suggesting a possible therapeutic approach for PKD," explained Dr. Freedman. "This was the first time induced pluripotent stem cells have been used to study human kidney disease where a defect related to disease mechanisms has been found."

The researchers noted that reprogrammed stem cells from patients with ADPKD may also be useful for testing new therapeutics before trying them out in humans.

In an accompanying editorial, Alexis Hofherr, MD and Michael Köttgen, MD (University Medical Centre, in Freiburg, Germany) stated that the study has "laid the groundwork for using induced pluripotent in PKD research. This important step forward will provide novel opportunities to model PKD pathogenesis with human cells with defined patient mutations."

More information: The article, entitled "Reduced Ciliary Polycystin-2 in iPS Cells from PKD Patients with PKD1 Mutations," will appear online on September 5, 2013, DOI: 10.1681/ASN.2012111089.

The editorial, entitled "Induced Pluripotent Stem Cells from Polycystic Kidney Disease Patients: A Novel Tool to Model the Pathogenesis of Cystic Kidney Disease," will appear online on September 5, 2013, DOI: 10.1681/ASN.2013070767

add to favorites email to friend print save as pdf

Related Stories

Aurora A may contribute to kidney disease

Jun 13, 2011

The Aurora A kinase may contribute to polycystic kidney disease (PKD) by inactivating a key calcium channel in kidney cells, according to a study in the June 13 issue of The Journal of Cell Biology.

Gene mutations predict early, severe form of kidney disease

Oct 24, 2011

The most common kidney disease passed down through families, autosomal dominant polycystic kidney disease (ADPKD) affects one in 400 to 1,000 individuals and is characterized by cysts on the kidneys. The condition slowly ...

New drug target for kidney disease discovered

Apr 26, 2011

Two discoveries at UC Santa Barbara point to potential new drug therapies for patients with kidney disease. The findings are published in this week's issue of the Proceedings of the National Academy of Sciences.

Clues revealed to cause of deadly kidney disease in newborns

Oct 24, 2011

Babies born with autosomal recessive polycystic kidney disease (ARPKD) often develop kidney failure because they have very large kidneys filled with tiny cysts. Even with excellent medical care, about 30% die shortly after ...

Recommended for you

Overwhelmed west Africa ramps up Ebola response

11 hours ago

West Africa intensified its response to the deadly Ebola epidemic on Sunday, with Sierra Leone uncovering scores of dead bodies during a 72-hour shutdown and Liberia announcing hundreds of new hospital beds.

Sierra Leone reaches final day of Ebola lockdown

14 hours ago

Frustrated residents complained of food shortages in some neighborhoods of Sierra Leone's capital on Sunday as the country reached the third and final day of a sweeping, unprecedented lockdown designed to ...

Sierra Leone faces criticism over Ebola shutdown

Sep 20, 2014

Sierra Leone began the second day of a 72-hour nationwide shutdown aimed at containing the spread of the deadly Ebola virus on Saturday amid criticism that the action was a poorly planned publicity stunt.

Presence of peers ups health workers' hand hygiene

Sep 19, 2014

(HealthDay)—The presence of other health care workers improves hand hygiene adherence, according to a study published in the October issue of Infection Control and Hospital Epidemiology.

User comments