Reproducing the pathophysiology of polycystic kidney disease from human
iPS cells
Understanding the pathogenesis of hereditary polycystic kidney disease
and developing new treatments

Date:
August 21, 2020
Source:
Kumamoto University
Summary:
A research project has successfully reproduced the pathogenesis of
autosomal dominant polycystic kidney disease (ADPKD) from human
iPS cells in vitro. Although cysts derived from renal tubules
have been previously documented, this is the first derivation of
cysts from collecting ducts, which is more closely related to the
pathogenesis of the disease. This research is expected to lead to
a better understanding of disease states and the development of
new treatment methods.



FULL STORY ========================================================================== Joint research, led by Kumamoto University in Japan, has successfully reproduced the pathogenesis of autosomal dominant polycystic kidney
disease (ADPKD) from human iPS cells in vitro. ADPKD is a disease that
causes multiple cysts in both kidneys and is the most common hereditary
kidney disease.

Although cysts derived from renal tubules have been previously documented,
this is the first induction of cysts from collecting ducts, which is
more closely related to the pathogenesis of the disease. The researchers
expect that this will lead to a better understanding of disease states
and the development of new treatment methods.


========================================================================== ADPKD is estimated to affect 1 in every 400-1,000 people. Although
half of ADPKD patients progress to renal failure by the age of 60, the underlying mechanisms of the disease are not clear and a treatment has
yet to be found.

ADPKD is caused by mutations in the PKD genes, and will develop if one
or both copies of the PKD genes, inherited from the father and mother
each, have mutations (heterozygous or homozygous mutations). The PKD
genes consist of PKD1 and PKD2 and about 85% of all ADPKD patients
have a heterozygous mutation of the PKD1 gene. The remaining 15% have
a heterozygous mutation of the PKD2 gene.

Those with heterozygous mutations of the PKD1 gene have a more severe prognosis, with approximately half developing renal failure by the age
60 due to the progression of renal cysts. The mechanism of ADPKD has
been mainly studied in mice. However, mice with a heterozygous mutation
in the PKD1 gene develop few renal cysts, even in adults, and human
symptoms are not reproduced.

Kidneys develop through the interactions between the two different
precursors; nephron progenitors and ureteric buds. Nephron progenitors differentiate into the renal tubules that reabsorb salt and water in
the urine, and ureteric buds differentiate into the collecting ducts
that collect urine and reabsorb water.

ADPKD cysts can originate from both the renal tubules and the collecting
ducts, but the collecting ducts appear to be their predominate origin. In
2014, Nishinakamura et al. reported on a method of inducing renal tubules
from human iPS cells via nephron progenitor cells. Since then, several
research groups have successfully produced renal tubule-derived cysts
from iPS cells that had a homozygous mutation of the PKD1 gene, but cysts derived from collecting ducts have not yet been produced. Because renal tubule-cysts have also been formed from normal iPS cells without gene
mutation, it was not possible to reproduce the disease state from iPS
cells derived from ADPKD patients who had the heterozygous mutation of
the PKD1 gene. However, Professor Nishinakamura's research group induced collecting ducts from human iPS cells via ureteric buds in 2017, and
have since been attempting to reproduce cysts derived from collecting
duct by building on their own methods.

To reproduce the ADPKD cysts, the researchers used the gene editing
technology CRISPR-Cas9 to create both homozygous and heterozygous mutant
iPS cells with the PKD1 gene and induced them into renal tubules. After administration of a drug called forskolin, which activates a factor that exacerbates ADPKD cysts, tubular cysts were reproduced as in previous
reports. However, mild cysts also formed from the renal tubules that
had not been genetically mutated.

When these iPS cells were induced into collecting ducts and treated
with forskolin, cysts formed from the collecting duct that had the
PKD1 homozygous mutation. On the other hand, cysts did not form from
collecting ducts that had no gene mutations, indicating that their
response to forskolin was different from that of renal tubules. When researchers checked the expression of the receptor for the antidiuretic
hormone vasopressin, which acts on the collecting duct, they found that
it was only expressed in the collecting duct. Vasopressin is known to exacerbate ADPKD cysts from collecting ducts, and when it was administered
to the induced collecting ducts and renal tubules, cysts formed, albeit
at a low frequency, only in collecting ducts with PKD1 homozygous
mutation. Furthermore, cysts partially formed in collecting ducts with
the PKD1 heterozygous mutation after administration of forskolin. When
iPS cells from an ADPKD patient with the PKD1 heterozygous mutation were
used to induce collecting ducts, cysts formed in the same way. According
to the researchers, this is the first successful reproduction of ADPKD
disease pathology from patient-derived iPS cells.

"This study shows that the method of inducing collecting ducts from iPS
cells can be a new disease model for ADPKD," said study leader, Professor Nishinakamura. "By analyzing these collecting duct cysts -- which are
similar to actual clinical conditions -- we may find mechanisms and
develop new therapeutic methods that have been difficult to identify until
now. We also expect that the replication of cysts from patient-derived
iPS cells will lead to research and treatments for individual cases."

========================================================================== Story Source: Materials provided by Kumamoto_University. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Shohei Kuraoka, Shunsuke Tanigawa, Atsuhiro Taguchi, Akitsu Hotta,
Hitoshi Nakazato, Kenji Osafune, Akio Kobayashi, Ryuichi
Nishinakamura.

PKD1-Dependent Renal Cystogenesis in Human Induced Pluripotent
Stem Cell- Derived Ureteric Bud/Collecting Duct Organoids. Journal
of the American Society of Nephrology, 2020; ASN.2020030378 DOI:
10.1681/asn.2020030378 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200821094825.htm

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