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Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression

Standard

Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression. / Akbari, Masaw; West, Jonathan D; Doerr, Nicholas; Kipp, Kevin R; Marhamati, Neda; Vuong, Sabrina; Wang, Yidi; Rinschen, Markus M; Talbot, Jeffrey J; Wessely, Oliver; Weimbs, Thomas.

In: P NATL ACAD SCI USA, Vol. 119, No. 30, e2121267119, 26.07.2022.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Akbari, M, West, JD, Doerr, N, Kipp, KR, Marhamati, N, Vuong, S, Wang, Y, Rinschen, MM, Talbot, JJ, Wessely, O & Weimbs, T 2022, 'Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression', P NATL ACAD SCI USA, vol. 119, no. 30, e2121267119. https://doi.org/10.1073/pnas.2121267119

APA

Akbari, M., West, J. D., Doerr, N., Kipp, K. R., Marhamati, N., Vuong, S., Wang, Y., Rinschen, M. M., Talbot, J. J., Wessely, O., & Weimbs, T. (2022). Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression. P NATL ACAD SCI USA, 119(30), [e2121267119]. https://doi.org/10.1073/pnas.2121267119

Vancouver

Akbari M, West JD, Doerr N, Kipp KR, Marhamati N, Vuong S et al. Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression. P NATL ACAD SCI USA. 2022 Jul 26;119(30). e2121267119. https://doi.org/10.1073/pnas.2121267119

Bibtex

@article{a2c887bc3e204b92be223eaaf998761e,
title = "Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression",
abstract = "Autosomal dominant polycystic kidney disease (ADPKD) affects more than 500,000 individuals in the United States alone. In most cases, ADPKD is caused by a loss-of-function mutation in the PKD1 gene, which encodes polycystin-1 (PC1). Previous studies reported that PC1 interacts with atypical protein kinase C (aPKC). Here we show that PC1 binds to the ζ isoform of aPKC (PKCζ) and identify two PKCζ phosphorylation sites on PC1's C-terminal tail. PKCζ expression is down-regulated in patients with ADPKD and orthologous and nonorthologous PKD mouse models. We find that the US Food and Drug Administration-approved drug FTY720 restores PKCζ expression in in vitro and in vivo models of polycystic kidney disease (PKD) and this correlates with ameliorated disease progression in multiple PKD mouse models. Importantly, we show that FTY720 treatment is less effective in PKCζ null versions of these PKD mouse models, elucidating a PKCζ-specific mechanism of action that includes inhibiting STAT3 activity and cyst-lining cell proliferation. Taken together, our results reveal that PKCζ down-regulation is a hallmark of PKD and that its stabilization by FTY720 may represent a therapeutic approach to the treat the disease.",
keywords = "Animals, Disease Models, Animal, Disease Progression, Enzyme Activation, Fingolimod Hydrochloride/pharmacology, Humans, Mice, Polycystic Kidney, Autosomal Dominant/drug therapy, Protein Kinase C/metabolism, TRPP Cation Channels/genetics",
author = "Masaw Akbari and West, {Jonathan D} and Nicholas Doerr and Kipp, {Kevin R} and Neda Marhamati and Sabrina Vuong and Yidi Wang and Rinschen, {Markus M} and Talbot, {Jeffrey J} and Oliver Wessely and Thomas Weimbs",
year = "2022",
month = jul,
day = "26",
doi = "10.1073/pnas.2121267119",
language = "English",
volume = "119",
journal = "P NATL ACAD SCI USA",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "30",

}

RIS

TY - JOUR

T1 - Restoration of atypical protein kinase C ζ function in autosomal dominant polycystic kidney disease ameliorates disease progression

AU - Akbari, Masaw

AU - West, Jonathan D

AU - Doerr, Nicholas

AU - Kipp, Kevin R

AU - Marhamati, Neda

AU - Vuong, Sabrina

AU - Wang, Yidi

AU - Rinschen, Markus M

AU - Talbot, Jeffrey J

AU - Wessely, Oliver

AU - Weimbs, Thomas

PY - 2022/7/26

Y1 - 2022/7/26

N2 - Autosomal dominant polycystic kidney disease (ADPKD) affects more than 500,000 individuals in the United States alone. In most cases, ADPKD is caused by a loss-of-function mutation in the PKD1 gene, which encodes polycystin-1 (PC1). Previous studies reported that PC1 interacts with atypical protein kinase C (aPKC). Here we show that PC1 binds to the ζ isoform of aPKC (PKCζ) and identify two PKCζ phosphorylation sites on PC1's C-terminal tail. PKCζ expression is down-regulated in patients with ADPKD and orthologous and nonorthologous PKD mouse models. We find that the US Food and Drug Administration-approved drug FTY720 restores PKCζ expression in in vitro and in vivo models of polycystic kidney disease (PKD) and this correlates with ameliorated disease progression in multiple PKD mouse models. Importantly, we show that FTY720 treatment is less effective in PKCζ null versions of these PKD mouse models, elucidating a PKCζ-specific mechanism of action that includes inhibiting STAT3 activity and cyst-lining cell proliferation. Taken together, our results reveal that PKCζ down-regulation is a hallmark of PKD and that its stabilization by FTY720 may represent a therapeutic approach to the treat the disease.

AB - Autosomal dominant polycystic kidney disease (ADPKD) affects more than 500,000 individuals in the United States alone. In most cases, ADPKD is caused by a loss-of-function mutation in the PKD1 gene, which encodes polycystin-1 (PC1). Previous studies reported that PC1 interacts with atypical protein kinase C (aPKC). Here we show that PC1 binds to the ζ isoform of aPKC (PKCζ) and identify two PKCζ phosphorylation sites on PC1's C-terminal tail. PKCζ expression is down-regulated in patients with ADPKD and orthologous and nonorthologous PKD mouse models. We find that the US Food and Drug Administration-approved drug FTY720 restores PKCζ expression in in vitro and in vivo models of polycystic kidney disease (PKD) and this correlates with ameliorated disease progression in multiple PKD mouse models. Importantly, we show that FTY720 treatment is less effective in PKCζ null versions of these PKD mouse models, elucidating a PKCζ-specific mechanism of action that includes inhibiting STAT3 activity and cyst-lining cell proliferation. Taken together, our results reveal that PKCζ down-regulation is a hallmark of PKD and that its stabilization by FTY720 may represent a therapeutic approach to the treat the disease.

KW - Animals

KW - Disease Models, Animal

KW - Disease Progression

KW - Enzyme Activation

KW - Fingolimod Hydrochloride/pharmacology

KW - Humans

KW - Mice

KW - Polycystic Kidney, Autosomal Dominant/drug therapy

KW - Protein Kinase C/metabolism

KW - TRPP Cation Channels/genetics

U2 - 10.1073/pnas.2121267119

DO - 10.1073/pnas.2121267119

M3 - SCORING: Journal article

C2 - 35867829

VL - 119

JO - P NATL ACAD SCI USA

JF - P NATL ACAD SCI USA

SN - 0027-8424

IS - 30

M1 - e2121267119

ER -