Experimental Research On The Treatment Of Autosomal Dominant Polycystic Kidney Disease With PPARγ Agonists

Objective:To investigate the efficacy and mechenism of PPAR-γ agonists on autosomal dominant polycystic kidney disease(ADPKD). Methods: PPAR-γ expression in different genotypes of Han:SPRD rat kidney tissues, cyst-lining epithelia, human kidney cortex cell line(HKC) are studied by RT-PCR and immunohistochemistry. Effect of proliferation, apoptosis and extracellular matrix secretion of PPAR-γ agonists on cyst-lining epithelia and HKC cell line co-transfected by PPAR-γ/RXR-a. full-length plasmids are explored by BrdU assay, FACS, real-time PCR and ELISA in vitro. The efficacy, safety and possible mechanisms of PPAR-γ agonists therapy are evaluated in vivo. Results: PPAR-γ is over-expressed in the kidney cortex of Han:SPRD heterozygote rats and significantly correlates with interstitial inflammation fibrosis marker and histologic changes. PPAR-γ agonists are able to inhibit proliferation and promote apoptosis of ADPKD cyst-lining epithelia in dose-dependent manner as well as decrease the secretion of extracellular matrix. After co-transfection of PPAR-γ and RXR-a full-length plasmids, HKC cell line can demonstrate similar effect. Rosiglitazone therapy can retard the progression of male heterozygote (Cy/+) rats and pkd2^WS25/- mice, significantly prolong the survival. But it still displays some side effects such as fluid retention, which may lead to volume overload and aggravate the heart failure. Novel PPARγ agonists and combination therapy may reduce the risk and hold a better perspective in clinical studies.