Kidney Week

Abstract: SA-PO512

Proteomic Analysis for the Identification of the PKD1 Related Signaling Pathways and Direct Targeting of Polycystic Kidney and Liver Disease: Few Cysts Remain Uncontrolled

Session Information

• ADPKD: Clinical Studies
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1001 Genetic Diseases of the Kidney: Cystic

Authors

• Cordido, Adrian, Health Research Institute of Santiago de Compostela (IDIS)., Santiago de Compostela, GAL, Spain

Adrian Cordido,

• Garcia-Gonzalez, Miguel A., Health Research Institute of Santiago de Compostela (IDIS)., Santiago de Compostela, GAL, Spain

Miguel A. Garcia-Gonzalez,

• Vizoso, Marta, Health Research Institute of Santiago de Compostela (IDIS)., Santiago de Compostela, GAL, Spain

Marta Vizoso,

• Calviño, Vanesa, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

Vanesa Calviño,

• Diaz-Rodriguez, Candido, University Clinical Hospital of Santiago de Compostela (CHUS), Santiago de Compostela, Spain

Candido Diaz-Rodriguez,

• Bravo, Susana, Health Research Institute of Santiago de Compostela (IDIS)., Santiago de Compostela, GAL, Spain

Susana Bravo,

Background

Different mechanisms have been related to the pathogenesis of renal and hepatic cystogenesis but the identification of the proteome signature for the identification of the cystogenic fingerprint and consequent treatment approaches has never been develop up to date.

Methods

We inactivated Pkd1 (Pkd1^cond/condTamCre) gene at postnatal day 10/11 (cystic window) and postnatal day 15/16 (non-cystic window) and recollected organs at day 30 for kidney (cystic kidney proteome or CKP) and liver (cystic liver proteome or CLP) proteome analysis by mass spectrometry MALDI-TOF. We refined the renal and hepatic cystogenic proteome (Reactome, KEGG, FunRich, String) by the identification of 34 specific proteins related to the liver phenotype (26 up and 8 down) and 22 to the kidney phenotype (16 up and 6 down).

Results

As expected, the major pathways related to CKP and CLP are signal transduction, immune system, metabolism and metabolism of proteins. Interestingly, vesicle-mediated transport and cell cycle pathways are specifically related to CLP and, in contrast, extracellular matrix organization and developmental biology pathways are specific of CKP. Based on this and previous results, approach treatment of PKD animals allowing us to inhibition of liver cystogenesis and significantly reduction of kidney cystic index and volume, recovering physiological parameters of kidney and liver function. In addition, we combined our molecules with known therapies for ADPKD (Tolvaptan) showing recovery of kidney and liver physiological parameters, although THP-positive nephron segment and a low portion of DBA positive remain cystic. This indicates the need of continuing puzzling out the remaining cysts for further treatments.

Conclusion

We described a list of new signaling pathways and possible targets for the development of specific therapeutic approaches for renal and hepatic phenotypes related to ADPKD. This data opens a new understanding of the molecular basis of the disease based on an organ specific protein profile of cystogenesis.