Abstract: TH-PO0381
HTRA1 Deficiency Worsens Adriamycin-Induced Glomerulosclerosis in a Mouse Model
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Wikan, Naruemon, University of Utah Health, Salt Lake City, Utah, United States
- Mueangaun, Sirikul, Chiang Mai University, Chiang Mai, Thailand
- Huang, Yufeng, University of Utah Health, Salt Lake City, Utah, United States
- Beamish, Jeffrey A., University of Michigan, Ann Arbor, Michigan, United States
- Naik, Abhijit S., 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 Joho Kagaku Ryoiki, Ikoma, Nara Prefecture, Japan
- Al-Rabadi, Laith, University of Utah Health, Salt Lake City, Utah, United States
Background
Adriamycin-induced nephropathy is a well-established experimental model of podocyte injury and nephrotic syndrome that recapitulates key features of progressive proteinuric kidney disease and glomerulosclerosis. HTRA1 is a secreted serine protease implicated in extracellular matrix remodeling and tissue injury responses, but its role in chronic podocyte injury remains incompletely defined.
Methods
Ten-week-old male BALB/c wild-type (WT) and HTRA1-knockout mice (KO) received a single tail vein injection of Adriamycin at 5 mg/kg. Renal injury was assessed by 24-hour urinary protein and albumin excretion, kidney histology, and immunoblot analysis of purified glomeruli. We evaluated podocyte slit diaphragm integrity, inflammatory and profibrotic signaling, extracellular matrix accumulation, and endoplasmic reticulum stress.
Results
Following Adriamycin administration, HTRA1 KO developed significantly greater proteinuria and albuminuria than WT mice. HTRA1 deficiency was associated with more severe disruption of the glomerular filtration barrier, with reduced expression of key slit diaphragm and junctional proteins, including Nephrin, Podocin, ZO-1, and Occludin. Purified glomeruli from HTRA1 KO mice showed enhanced inflammatory and profibrotic responses, with increased expression of TLR4, NLRP3, TGF-β1, and α-SMA. Histologic assessment demonstrated greater extracellular matrix accumulation and glomerular injury in HTRA1 KO mice. These changes were accompanied by altered ER stress signaling, including changes in BiP/GRP78 expression, consistent with accelerated progression of glomerulosclerosis.
Conclusion
HTRA1 deficiency exacerbates Adriamycin-induced glomerular injury by destabilizing podocyte structural integrity and amplifying inflammatory, profibrotic, and stress-related pathways. These findings support a protective role for HTRA1 in maintaining glomerular homeostasis and suggest that loss of HTRA1 activity may accelerate progression toward glomerulosclerosis.
Funding
- NIDDK Support