Polycystic kidney disease (PKD) is an important cause of end stage renal disease, but treatment options are limited. While later stages of the disease have been extensively studied, mechanisms driving the initial conversion of renal tubules into cysts are not understood. To identify factors that promote the initiation of cysts we deleted polycystin-2 (Pkd2) in mice and surveyed transcriptional changes before and immediately after cysts developed. We identified 74 genes which we term cyst initiation candidates (CICs). To identify conserved changes with relevance to human disease we compared these murine CICs to single cell transcriptomic data derived from patients with PKD and from healthy controls. Tumor-associated calcium signal transducer 2 (Tacstd2) stood out as an epithelial-expressed gene whose levels were elevated prior to cystic transformation and further increased with disease progression. Human tissue biopsies and organoids show that TACSTD2 protein is low in normal kidney cells but is elevated in cyst lining cells. While TACSTD2 has not been studied in PKD, it has been studied in cancer where it is highly expressed in solid tumors while showing minimal expression in normal tissue. This property is being exploited by antibody drug conjugates that target TACSTD2 for the delivery of cytotoxic drugs. Our finding that Tacstd2 is highly expressed in cysts, but not normal tissue, suggests that it should be explored as a candidate for drug development in PKD. More immediately, our work suggests that PKD patients undergoing TACSTD2 treatment for cancer should be monitored for kidney effects.

The authors have declared no competing interest.

Work was supported by DK103632 and GM060992 to GJP. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Human kidney tissue samples from nephrectomized kidneys were received from the Maryland PKD Research and Translational Core Center (part of the NIDDK U54 PKD-RRC). Human sample use was reviewed by the University of Maryland School of Medicine Institutional Review Board (IRB) and determined not to be human research, requiring no further IRB review. Thus, the Ethics Committee/IRB of the University School of Medicine waived ethical approval of this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus (49) and are accessible through GEO Series accession numbers: GSE222610 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE222610) GSE220322 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE220322). Reviewer token for miRNA (GSE222610) is idubgqkedfexraz and for mRNA (GSE220322) is ifoniomibbshbkb.