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The role of DNA damage as a therapeutic target in autosomal dominant polycystic kidney disease

Published online by Cambridge University Press:  26 November 2019

Jennifer Q. J. Zhang Open the ORCID record for Jennifer Q. J. Zhang [Opens in a new window] ,
Sayanthooran Saravanabavan ,
Alexandra Munt ,
Annette T. Y. Wong ,
David C. Harris ,
Peter C. Harris ,
Yiping Wang  and
Gopala K. Rangan
Jennifer Q. J. Zhang*
Affiliation:
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, SydneyNSW2145, Australia Department of Renal Medicine, Westmead Hospital, SydneyNSW2145, Australia
Sayanthooran Saravanabavan
Affiliation:
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, SydneyNSW2145, Australia Department of Renal Medicine, Westmead Hospital, SydneyNSW2145, Australia
Alexandra Munt
Affiliation:
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, SydneyNSW2145, Australia Department of Renal Medicine, Westmead Hospital, SydneyNSW2145, Australia
Annette T. Y. Wong
Affiliation:
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, SydneyNSW2145, Australia Department of Renal Medicine, Westmead Hospital, SydneyNSW2145, Australia
David C. Harris
Affiliation:
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, SydneyNSW2145, Australia Department of Renal Medicine, Westmead Hospital, SydneyNSW2145, Australia
Peter C. Harris
Affiliation:
Mayo Clinic Pirnie Translational Polycystic Kidney Disease Center, Mayo Clinic, Rochester, MN55905, USA
Yiping Wang
Affiliation:
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, SydneyNSW2145, Australia Department of Renal Medicine, Westmead Hospital, SydneyNSW2145, Australia
Gopala K. Rangan
Affiliation:
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, SydneyNSW2145, Australia Department of Renal Medicine, Westmead Hospital, SydneyNSW2145, Australia
*
Author for correspondence: Jennifer Q. J. Zhang, E-mail: [email protected]
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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is caused by heterozygous germ-line mutations in either PKD1 (85%) or PKD2 (15%). It is characterised by the formation of numerous fluid-filled renal cysts and leads to adult-onset kidney failure in ~50% of patients by 60 years. Kidney cysts in ADPKD are focal and sporadic, arising from the clonal proliferation of collecting-duct principal cells, but in only 1–2% of nephrons for reasons that are not clear. Previous studies have demonstrated that further postnatal reductions in PKD1 (or PKD2) dose are required for kidney cyst formation, but the exact triggering factors are not clear. A growing body of evidence suggests that DNA damage, and activation of the DNA damage response pathway, are altered in ciliopathies. The aims of this review are to: (i) analyse the evidence linking DNA damage and renal cyst formation in ADPKD; (ii) evaluate the advantages and disadvantages of biomarkers to assess DNA damage in ADPKD and finally, (iii) evaluate the potential effects of current clinical treatments on modifying DNA damage in ADPKD. These studies will address the significance of DNA damage and may lead to a new therapeutic approach in ADPKD.

Keywords

Autosomal dominantciliopathiesDNA damageDNA damage response pathwaypolycystic kidney disease
Type
Unsolicited Review
Information
Expert Reviews in Molecular Medicine , Volume 21 , 2019 , e6
Copyright
Copyright © Cambridge University Press 2019

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