PPARγ: New insights into its role in urothelial differentiation and regeneration

Urothelium functions as a urinary barrier against toxic materials in the urine. In urothelium, the cells are mitotically-quiescent, but remain able to proliferate in response to damage, or when cultured in vitro. The nuclear receptor, peroxisome proliferator activated receptor gamma (PPARγ), is implicated in urothelial differentiation and cancer, but underlying mechanism remains unclear. Firstly, the analysis of the human urothelial transcriptome revealed that PPARG1 encoding protein isoform 1 is expressed by urothelial cells and regulates the differentiation process. Subcellular extraction results verified that PPARγ acts as a nuclear DNA-bound nuclear receptor during early stages after initiation of differentiation, but shows an alternative non-chromatin bound role in differentiated NHU cells. The research then investigated the role for PPARγ in differentiated urothelial cells and found inhibition of PPARγ negatively regulates the regeneration process by attenuating the nuclear localization of pSMAD3. In conclusion, PPARγ protein isoform 1 was identified to act as nuclear receptor to regulate NHU cell differentiation but obtains an alternative non-chromatin-bound role for NHU cell regeneration. The switch of its compartmentalization in the nucleus might helps to maintain the balance of proliferation and differentiation in NHU cells