Abstract: PO2500
Proximal Tubule Cyclophilin D Mediates Kidney Fibrogenesis in Obstructive Nephropathy
Session Information
- CKD: Metabolism, Epigenetics, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Jang, Hee-Seong, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Noh, Mira, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Padanilam, Babu J., Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background
Proximal tubule (PT) is highly vulnerable to acute injury, including ischemic insult and nephrotoxins, and chronic kidney injury. It is established that PT injury is a primary cause of development of chronic kidney disease, but the underlying molecular mechanism remains to be defined.
Methods
Here, we tested whether PT cyclophilin D (CypD), a mitochondrial matrix protein, is a critical factor to cause kidney fibrosis progression. To define the role of CypD in kidney fibrosis, we used an established mouse model for kidney fibrosis, unilateral ureteral obstruction (UUO) model in global and PT-specific CypD knockout (KO).
Results
Global CypD KO blunted kidney fibrosis progression with inhibition of myofibroblast activation and fibrosis. UUO-induced tubular atrophy was suppressed in kidneys of global CypD KO, but not tubular dilation or apoptotic cell death. PT cell cycle arrest was highly increased in WT-UUO kidneys, but markedly attenuated in global CypD KO-UUO kidneys. The number of macrophages and neutrophils was less in UUO kidneys of global CypD KO than those of WT. The pro-inflammatory and -fibrotic factors were all inhibited in global CypD KO. In line with those of global CypD KO, PT-specific CypD KO also blunted kidney fibrosis progression, along with less tubular atrophy, renal parenchymal loss, cell cycle arrest in PT and inflammation, indicating a critical role for PT CypD in fibrogenesis.
Conclusion
Collectively, our data demonstrate that CypD in PT is a critical factor contributing to kidney fibrosis in UUO, providing a new paradigm for mitochondria-targeted therapeutics of fibrotic diseases.
Funding
- NIDDK Support