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Proximal tubule cyclophilin D mediates kidney fibrogenesis in obstructive nephropathy.
- Source :
-
American Journal of Physiology: Renal Physiology . Oct2021, Vol. 321 Issue 4, pF431-F442. 12p. - Publication Year :
- 2021
-
Abstract
- The proximal tubule (PT) is highly vulnerable to acute injury, including ischemic insult and nephrotoxins, and chronic kidney injury. It has been established that PT injury is a primary cause of the development of chronic kidney disease, but the underlying molecular mechanism remains to be defined. 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: the unilateral ureteral obstruction (UUO) model in global and PT-specific CypD knockout (KO). 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 wild-type UUO kidneys but was 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 wild-type kidneys. Proinflammatory and profibrotic factors were all inhibited in global CypD KO. In line with those of global CypD KO, PTspecific 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. Collectively, our data demonstrate that CypD in the PT is a critical factor contributing to kidney fibrosis in UUO, providing a new paradigm for mitochondria-targeted therapeutics of fibrotic diseases. [ABSTRACT FROM AUTHOR]
- Subjects :
- *RENAL fibrosis
*KIDNEY diseases
*CYCLOPHILINS
*KIDNEYS
*LABORATORY mice
Subjects
Details
- Language :
- English
- ISSN :
- 1931857X
- Volume :
- 321
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- American Journal of Physiology: Renal Physiology
- Publication Type :
- Academic Journal
- Accession number :
- 153059596
- Full Text :
- https://doi.org/10.1152/ajprenal.00171.2021