Abstract
Adult-Onset Conditional Deletion of Pkd1 and Tulp3 in Mice Exert Different Effects on Kidney Cyst Formation and Mitochondria Phenotypes: FR-PO596
Journal of the American Society of Nephrology, Vol.35(10S)
10/2024
DOI: 10.1681/ASN.2024d12p7s55
Abstract
Background:
Mutations on PKD1 and PKD2 coding for PC1 and PC2 cause ADPKD. PC1 and PC2 are widely expressed in multiple subcellular locations. Tulp3 (Tubby-like protein-3) is an adaptor protein that traffics membrane proteins including PC1 and PC2 into cilia. A previous study reported that mice with adult-onset deletion of Tulp3 develop mild cysts at 42 weeks old, much delayed than mice with deletion of Pkd1 or Pkd2. Metabolic reprogramming is an important modifier of ADPKD cystogenesis. The cause of mitochondrial dysfunction in ADPKD remains elusive. Here, we performed side-by-side comparison on kidney cyst and mitochondria phenotypes in mice with adult-onset deletion of Pkd1 & Tulp3 gene, respectively.
Methods:
Mice 4- to 6-week-old carrying Pax8-LC1 allele and homozygous Pkd1-floxed allele or Tulp3-floxed allele were treated with doxycycline for 10 days. Kidneys were harvested from mice 16-20 weeks after Doxy induction for analysis of cyst formation and ciliary expression of PC’s by H&E-stained histology and immunofluorescent staining, for mitochondria morphology by TEM, and for mito DNA mass and regulator gene expression by RT- PCR.
Results:
In mice 14 weeks after Pkd1 deletion vs control, kidneys showed markedly increased cyst index. TEM showed altered mitochondria morphology including decreased mitochondria area, perimeter, cristae number and density, and increased roundness. About 60% mitochondria surface was in contact with ER forming mitochondria-associated ER membranes (MAMs). The distance between ER-mitochondria contact was increased and the length of contact was decreased in Pkd1-cKO. These changes began in precystic stages (4 weeks after Doxy). In contrast, Tulp3-deleted kidneys had relatively normal mitochondria morphology and no cysts. PC1 and PC2 were absent in cilia, but present in extra-ciliary locations of Tulp3-deleted mice. Mitochondria master regulators PGC1α and PPARα, and DNA mass were reduced in Pkd1-deleted kidneys but unchanged in Tulp3-deleted.
Conclusion:
Loss of PC1 and PC2 in primary cilia of Tulp3-deleted mice is not sufficient for kidney cyst formation and mitochondria morphological changes as in Pkd1-deleted mice. Extraciliary polycystins are also important. Alternatively, other factors lost in Tulp3-deleted mice may protect against cystogenesis.
Details
- Title: Subtitle
- Adult-Onset Conditional Deletion of Pkd1 and Tulp3 in Mice Exert Different Effects on Kidney Cyst Formation and Mitochondria Phenotypes: FR-PO596
- Creators
- Biswajit PadhyJian XieDanish IdreesChou-Long Huang
- Resource Type
- Abstract
- Publication Details
- Journal of the American Society of Nephrology, Vol.35(10S)
- Publisher
- AMER SOC NEPHROLOGY; WASHINGTON
- DOI
- 10.1681/ASN.2024d12p7s55
- ISSN
- 1046-6673
- eISSN
- 1533-3450
- Grant note
- NIDDK
NIDDK Support
- Language
- English
- Date published
- 10/2024
- Academic Unit
- Internal Medicine; Nephrology
- Record Identifier
- 9984740959602771
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