Background
Alport syndrome is a genetic kidney disease caused by mutation in any of the COL4A3, COL4A4, or COL4A5 genes encoding the type IV collagen α3, α4, and α5 chains. Defects of type IV collagen α3α4α5 cause glomerular basement membrane abnormalities and lead to defects in glomerular filtration and ESKD. Treatment with angiotensin-converting enzyme inhibitors (ACEis) dramatically slows disease progression but does not stop progression to renal failure. Therefore, novel therapeutic options with different modes of action from ACEis are needed. Peroxisome proliferator-activated receptor (PPAR) δ agonists have shown renoprotective effects in several acute kidney injury mouse models. In this study, we investigated the effects of a potent and selective PPARδ agonist, REN001 (formerly HPP593), in a mouse model of Alport syndrome.
Conclusions
These results indicate that REN001 slows kidney disease progression in Alport mice. REN001 has a different mechanism of action from ACEis, so we, therefore, hypothesize that combining the two treatments may show additive effects to attenuate renal injury and slow progression to renal failure.
Methods
We administered REN001 from the early stages to the late stages of disease by once daily intraperitoneal injections.
Results
REN001 treatment halved proteinuria at the late stages of disease in Col4a3−/− mice. BUN levels were also decreased, and histological and molecular analyses showed that REN001 ameliorated renal inflammation and fibrosis. Conclusions: These results indicate that REN001 slows kidney disease progression in Alport mice. REN001 has a different mechanism of action from ACEis, so we, therefore, hypothesize that combining the two treatments may show additive effects to attenuate renal injury and slow progression to renal failure.
Trial registration
ClinicalTrials.gov NCT01613118.