Kidney Week

Abstract: FR-PO636

Pparg Pathway Drives Renal Uroplakin Cell Formation and Parenchymal Preservation During Urinary Tract Obstruction

Session Information

• Pediatric Nephrology - II
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

• 1900 Pediatric Nephrology

Authors

• Alharakeh, Mohammad, Nationwide Children's Hospital, Columbus, Ohio, United States

Mohammad Alharakeh,

• Grounds, Kelly, Nationwide Children's Hospital, Columbus, Ohio, United States

Kelly Grounds,

• Rodriguez, Felipe, Nationwide Children's Hospital, Columbus, Ohio, United States

Felipe Rodriguez,

• Li, Birong, Nationwide Children's Hospital, Columbus, Ohio, United States

Birong Li,

• Cortado, Hanna H., Nationwide Children's Hospital, Columbus, Ohio, United States

Hanna H. Cortado,

• Becknell, Brian, Nationwide Children's Hospital, Columbus, Ohio, United States

Brian Becknell,

• Jackson, Ashley R., Nationwide Children's Hospital, Columbus, Ohio, United States

Ashley R. Jackson,

Background

Urinary Tract Obstruction (UTO) is a leading cause of chronic and end stage kidney disease in children. While no current treatments prevent obstruction-induced kidney disease, future therapies may be identified by understanding how the kidney adapts to obstruction. We previously reported that obstruction triggers the formation of protective uroplakin (Upk) cells which preserve renal parenchyma during congenital and acquired UTO. The molecular program that governs Upk cell formation in the renal urothelium is unknown. In bladder, the Pparg signaling pathway drives urothelial differentiation. Thus, we hypothesized thatPparg drives renal Upk cell formation during UTO.

Methods

Kidneys from embryonic (E-) and postnatal (P-) female and male mice were collected. We modeled UTO using congenital and surgical models. We conditionally manipulated Pparg in Upk cells using inducible Pparg deletion (Upk2^iCre;Pparg^LOF) and gain-of-function (Upk2^iCre;Pparg^GOF) mouse lines. Immunofluorescent Analysis (IF-A) and renal ultrasound were used to evaluate the effect of Pparg pathway manipulation on UTO-induced Upk cell formation and renal parenchyma, respectively.

Results

Pparg was expressed by renal Upk cells at E17 - P7, but was absent in adult mice ≥P42. Both congenital and surgical UTO triggered Upk cells to re-express Pparg and its targets, Grhl3 and Fabp4. During UTO, Upk2^iCre;Pparg^LOF mice showed a significant reduction in Upk expression (10% Vs 3.1%, P=0.008) accompanied by significantly thinned renal parenchyma (30.9% Vs 25.9%, P=0.039), compared to Cre(-) mice. However, Upk2^iCre;Pparg^GOF mice induced a significant upregulation of Upk (10% Vs 17.42%, P=0.006) and exhibited significantly greater parenchymal preservation (30.9% Vs 44.4%, P=0.002), compared to Cre(-) mice.

Conclusion

Our results reveal that UTO-induced Pparg signaling is a recapitulation of a renal urothelium developmental program, and that Pparg signaling promotes Upk cell formation to preserve renal parenchyma during UTO. Our findings advance our understanding of renal adaptation to UTO and reveal a potential mechanism, such as Pparg signaling, with therapeutic utility for mitigating obstructive kidney disease in children. Future studies will investigate the utility of synthetic Pparg agonists during UTO.

Funding

• NIDDK Support