Autosomal Dominant polycystic Kidney Disease (ADpKD) is one of the most common monogenic disorders, characterized by the progressive formation of fluid-filled cysts. Tolvaptan is an approved drug for ADPKD patients, but is also associated with multiple side effects. The peroxisome proliferatoractivator receptor gamma (ppARγ) agonist pioglitazone slows disease progression in the pcK rat model for pKD. Here, we tested whether a combination treatment of relevant doses of tolvaptan and pioglitazone leads to improved efficacy in an adult-onset PKD mouse model. Tolvaptan indeed slowed PKD progression, but the combination treatment was not more effective than tolvaptan alone. In addition, although pioglitazone raised plasma levels of its surrogate drug marker adiponectin, the drug unexpectedly failed to slow PKD progression. The pioglitazone target PPARγ was expressed at surprisingly low levels in mouse, rat and human kidneys. other pioglitazone targets were more abundantly expressed, but this pattern was comparable across various species. The data suggest that several potential pharmacokinetic and pharmacodynamic (PK/PD) differences between different species may underlie whether or not pioglitazone is able to slow pKD progression. the ongoing phase ii clinical trial with low-dose pioglitazone treatment (NCT02697617) will show whether pioglitazone is a suitable drug candidate for ADpKD treatment. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic disorders, affecting 1 in 2500 individuals 1. The most prominent disease feature is the progressive formation of fluid-filled cysts, mainly in the kidneys and less frequent in liver and pancreas 2. In the majority of patients, the cause of disease is a mutation in the PKD1 (±85%) or PKD2 (±15%) gene, encoding for either polycystin-1 or polycystin-2 3,4. Although the exact mechanisms are not yet completely understood, both PKD1 and PKD2 mutations have been shown to dysregulate many intracellular signalling pathways including mammalian target of rapamycin (mTOR), 5' adenosine monophosphate-activated protein kinase (AMPK), transforming growth factor-beta (TGF-β) and extracellular signal-related kinase (ERK) 5-12. Also, altered fluid secretion involving the cystic fibrosis transmembrane conductance regulator (CFTR) and metabolic alterations (increased glycolysis and reduced fatty acid oxidation) have been reported to contribute to disease progression 13-16. Over the recent years, various interventions based on correcting dysregulated intracellular signalling have been tested in clinical trials 17-21. So far, only the vasopressin V2 receptor antagonist tolvaptan (Jinarc ®), which lowers intracellular cyclic AMP (cAMP) levels in the collecting duct segment of the kidney, was convincingly shown to slow disease progression in patients and is currently available in multiple countries as a treatment option 22-24. While tolvaptan is effective in delaying the loss of renal function, the drug is accompanied by side effects, including polyuria and liver ...