Kidney Week

Abstract: FR-PO724

New Therapeutic Approach Based in Inhibition of Metalloproteases in Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Clinical/Translational
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Cordido, Adrian, Instituto de Investigacion Sanitaria (IDIS) de Santiago de Compostela, Santiago de Compostela, Spain

Adrian Cordido,

• Rodríguez, Cándido Díaz, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain

Cándido Díaz Rodríguez,

• Carracedo, Angel, Fundación Publica Galega de Medicina Xenomica, Santiago de Compostela, Galicia, Spain

Angel Carracedo,

• Garcia-Gonzalez, Miguel A., Instituto de Investigacion Sanitaria (IDIS) de Santiago de Compostela, Santiago de Compostela, Spain

Miguel A. Garcia-Gonzalez,

Background

Polycystic Kidney Disease (PKD) is a group of genetic disorders characterized by the presence by multiple cysts in the renal parenchyma, as well as others extrarenal manifestations such as hepatic cysts (Polycystic Liver Disease or PLD). Mutations in genes PKD1 and PKD2 caused the dominant form called ADPKD, by other band mutation in PKHD1 caused the recessive form or ARPKD.
To this day, it have been reported several altered molecular pathways in the PKD but the key mechanism of cystogenesis (process by which cysts are formed) remains unmask. In that studio, with the use of animal models we reported a study about metalloproteases or MMPs of Extracellular Matrix (ECM) in the renal and hepatic cystogenesis and its therapeutic potential.

Methods

We use the rodent models Pkd1^cond/cond TamCre y Pkdh1^{del3-4/del3-4}, models of ADPKD and ARPKD respectively, as well as for the study at molecular level of the role of the MMPs, as models for the testing of a new therapeutic approach, called MTT.
Furthermore, the understanding of the disease has been addressed by histological (immunofluorescent and immunohistochemical), pathophysiological (renal and/or hepatic function) and transcriptomic (RT-qPCR) techniques.

Results

We have realized a complete study of the MMPs present in kidney and liver of our animal models, as well as have studied different pro-fibrotic and inflammatory markers related to the enzymatic activity of MMPs. Our study indicates that in renal and hepatic cystogenesis the levels of these markers and genetic expression of MMPs are increased, and therefore that this molecular pathway may be a possibility of therapeutic approach.
MTT is an inhibitor of the extracellular matrix metalloproteinases that our group wanted to test as a possible therapy for ADPKD and ARPKD. We have seen that MTT inhibits the gene expression of several MMPs, reduces renal and hepatic fibrosis, improves renal function and inhibits renal and hepatic cystogenesis.

Conclusion

In this work, we evaluate the role of matrix metalloproteases (MMPs) in the cystogenesis of PKD. In addition, the MMP inhibitor MTT was examined in two different rodent models reducing hepatic and renal cystogenesis, and offering a new possible approach.