Therapeutic opportunities in polycystic kidney and liver disease through extracellular matrix dynamics

Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease (ADPKD and ARPKD) are, respectively, common and rare forms of polycystic disorders, characterized by the formation and progressive growth of cysts from tubules in the kidneys and bile ducts in the liver. Alterations in the extracellular matrix (ECM) and in the activity of matrix metalloproteases (MMPs), both associated with fibrosis, have been shown to be important factors in cystic growth and progression of these diseases. We used tandem mass spectrometry (LC-MS/MS) to identify the most enriched proteins and pathways in an orthologous rapidly progressive mouse model of ADPKD: Pkd1^flox/floxTamCre. This information was used to discover and validate novel therapeutic targets in orthologous models of ADPKD (Pkd1^flox/floxTamCre) and ARPKD (Pkdh1^{del3-4/del3-4}). ECM related pathways and expression levels of MMPs were among the most dysregulated cellular processes in polycystic kidney and liver. Selective inhibition of MMPs by marimastat (MTT) altered the ECM response and resulted in inhibition of collecting duct-derived cyst growth, delay of global kidney cyst progression and rescue of liver phenotype by normalized MMPs expression and significant reduction in fibrosis. This phenotypic improvement was further enhanced by treatment of MTT and tolvaptan, indicating an additive benefit to targeting the fibrotic and growth pathways in cysts. As conclusion, targeting of MMPs are important in ECM dysregulation and offers a new potential therapeutic strategy for both kidney and bile duct derived fibrocystic disease in ADPKD and ARPKD. Such approaches can have additive benefits with other treatment approaches, such as tolvaptan.