(7) Pparg Promotes Uroplakin Expression During Congenital and Acquired Urinary Tract Obstruction.

Background: Urinary Tract Obstruction (UTO) is a leading cause of chronic and end stage kidney disease (CKD/ESKD) in children. Surgical indications are not always clear, and no treatment can prevent CKD/ESKD. However, heterogeneous patient outcomes implicate a renoprotective adaptation. Our lab discovered renal urothelium remodeling protects the obstructed kidney by increasing uroplakin (UPK) expression. Efforts to increase UPK may have therapeutic utility for patients with UTO. PPARG is known to regulate UPK expression but has not been investigated in renal urothelium. We hypothesize that PPARG promotes UPK expression in the renal urothelium during UTO.

Objectives: The objective of this work is to determine whether PPARG promotes UPK expression in the renal urothelium.

Design/Methods: R software was used to conduct bioinformatics analyses with data derived from a publicly available UUO time course. DEGs were identified and transcriptional regulators were predicted by ChEA3 within the Upk3a+ cluster. Kidneys were collected from normal, and surgically obstructed (UUO, unilateral ureteral obstruction) mice. PPARG was deleted (Upk2iCre;Ppargfl/fl [Pparg-LOF]) or activated (Upk2iCre;VP16-Ppargfl/+ [Pparg-GOF]) in UPK cells in mice with UUO. Immunofluorescent Analysis (IF-A) was used to evaluate renal urothelium and PPARG manipulation.

Results: We identified 78 DEGs among Upk3a+ cells in UUO compared to normal kidneys, and ChEA3 identified one upstream (KLF5) and three (ELF3, GRHL3, and FOXA1) downstream regulators of Pparg. We validated expression of KLF5, GRHL3 and FOXA1 in renal urothelium. PPARG was significantly increased in the renal urothelium of UUO compared to normal kidneys. Evaluation of Pparg-LOF and Pparg-GOF mice revealed that UPK is regulated by PPARG during UUO. Furthermore, GRHL3, but not FOXA1 was altered by genetic manipulation of PPARG.

Conclusion: Our results reveal that PPARG promotes UPK expression in the renal urothelium during UTO. Our findings advance our understanding of renal adaptation to UTO and reveal PPARG as a novel therapeutic target for patients with UTO. Future studies will interrogate upstream and downstream PPARG regulators, and whether pharmacological activation of PPARG mitigates UTO-induced kidney injury.