Introduction: Polycystic kidney disease (PKD) is a heterogeneous group of monogenic disorders characterized by the bilateral formation and progressive expansion of renal cyst. Several Mendelian diseases including Autosomal Dominant PKD (ADPKD) and Autosomal Recessive PKD (ARPKD) can be grouped under this pathological entity. PKD can be associated with several extrarenal manifestations; the most common of these are the presence of liver cysts (Polycystic Liver Disease [PLD]).

A number of different mechanisms have been related to pathogenesis of PKD. However, there is no effective therapy for this disease. Here, we focused on alteration in the extracellular matrix (ECM) and in the MTT, an inhibitor of the metalloproteinases of ECM, which is presented as a possible therapy for renal and hepatic phenotype of PKD.

Method: We have studied the effect of MTT in different animal models: Pkd1cond/condTamCre (ADPKD model) and Pkhd1del3-4/del3-4 (ARPKD model). Both mice are good characterized and known models in PKD field.

MTT was tested in the two mice, and after sacrifice kidney/livers and blood serum were collected for study with histological (immunohistochemistry and immunofluorescence) and biochemistry (analysis of renal and hepatic function) techniques.

Results: Our study shows the MTT as possible therapy for PKD. First: we have study the hepatic phenotype in Pkd1cond/condTamCre and Pkhd1del3-4/del3-4 mice and we saw an inhibition in hepatic cystogenesis for both models at level of parenchyma cysts and bile duct dilatations. Second: we have found that MTT inhibits, in a specifically way, cysts from the collecting duct of the nephron (DBA+ cysts) in the Pkd1cond/condTamCre mouse and that improves kidney function. Finally, we combined the MTT with Tolvaptan (Samsca®), the only therapy approved and commercialized for ADPKD. The combination between the two drugs proved a very significant improvement in renal cystogenesis and recovering the renal function.

Conclusions: With this work, we demonstrated the effectiveness of a novel therapy called MTT for PKD. We tested MTT in animal models seeing inhibition in hepatic cystogenesis and collecting duct cyst in renal phenotype. More interesting, the combination of MTT with Tolvaptan resulted in a potent therapeutic approach to block cystogenesis.