Abstract: FR-PO0181
HTRA1 Deficiency Affects Renal Adaptive Responses During AKI Transition to CKD
Session Information
- AKI: Mechanisms - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Wikan, Naruemon, University of Utah Health, Salt Lake City, Utah, United States
- Zimmerman, Michael A., University of Utah Health, Salt Lake City, Utah, United States
- Nwaduru, Chinedu Elvis, University of Utah Health, Salt Lake City, Utah, United States
- Naik, Abhijit S., University of Michigan, Ann Arbor, Michigan, United States
- Beamish, Jeffrey A., University of Michigan, Ann Arbor, Michigan, United States
- Beck, Laurence H., Boston University, Boston, Massachusetts, United States
- Oka, Chio, Nara Sentan Kagaku Gijutsu Daigakuin Daigaku Sentan Kagaku Gijutsu Kenkyuka Bioscience Ryoiki, Ikoma, Nara Prefecture, Japan
- Al-Rabadi, Laith, University of Utah Health, Salt Lake City, Utah, United States
Background
Ischemia-Reperfusion (I/R) is a common cause of acute kidney injury (AKI) with intrinsic renal adaptive mechanisms preventing progression towards fibrosis. Maladaptive response with sustained ischemia can lead to progressive renal fibrosis with worse renal outcomes. The dynamic changes of renal injury and adaptive response determine whether AKI will transition to CKD. HTRA1 expression and activity have been reported to increase with ischemia and may be involved in the renal adaptive response. HTRA1 cleaves extracellular matrix (ECM) substrates and is also well known to be an inhibitor of transforming growth factor (TGF-b1).
Methods
We performed renal pedicle clamping with 30 mins occlusion time followed by reperfusion. We assessed the dynamic changes in endoplasmic reticulum stress markers, fibrosis markers including α-SMA and TGF-b1 between male C57BL/6 WT and HTRA1-KO mice at different time points, day 1, 3, 14, and 28 after I/R exposure by using western blotting of kidney tissue from the clamped side. Moreover, we used ELISA kits for creatinine and KIM-1 levels in the blood.
Results
HTRA1 KO mice have more prolonged AKI in response to IR, compared to WT mice, as evident by tissue KIM1 significantly higher levels. Permanent damage of renal tubulointerstitial injury and irreversible fibrosis was obviously observed in HTRA1-KO mice, compared to WT. While KIM-1 surges at day 1 and starts to dampen in day 3, it was persistently elevated until day 28 in HTRA1-KO mice. This was associated with very early increase in α-SMA and TGF-b1 from day 1 and continues to be elevated at day 28 in HTRA1-KO mice as opposed to WT mice in which TGF-b1 and α-SMA start to show up at day 14.
Conclusion
HTRA1 may mediate adaptive response to IR and ameliorate the transition to a more fibrotic, CKD state.
Funding
- Private Foundation Support