Abstract: FR-PO290
Combined Transcriptome and Metabolome Profiling in a Mouse Model of Tuberous Sclerosis Complex Renal Cystic Disease
Session Information
- Genetic Diseases of the Kidneys: Cystic - II
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1101 Genetic Diseases of the Kidneys: Cystic
Authors
- Zahedi, Kamyar A., University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
- Barone, Sharon L., University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
- Brooks, Marybeth, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
- Soleimani, Manoocher, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
Background
Tuberous sclerosis complex (TSC) is an autosomal recessive disorder that is caused by mutations in hamartin (TSC1) or tuberin (TSC2) and affects over a million individuals worldwide. In the kidney, TSC is associated with the development of cysts and angiomyolipomata, which damage the renal parenchyma and lead to renal failure. The cyst development and expansion in principal cell specific Tsc1 knockout mice (Tsc1-cKO/Aqp2 Cre; Tsc1cKO) is dependent on the expansion of A-intercalated cells and diminution of principal cells. In order to identify the mRNA and metabolome changes associated with cystogenesis in TSC renal disease, we compared the transcriptome and metabolome of kidneys from 28 days old wildtype (Wt) and Tsc1cKO mice.
Methods
The transcriptome and metabolome of 28 days old Wt and Tsc1cKO were analyzed and compared.
Results
There were significant changes in the levels of 14 metabolites in the kidneys of Tsc1cKO mice compared to their Wt counterparts. These included reductions in the levels of a number of amino acids (e.g., Gly, Ile, leu, Trp and valine). We also observed significant decreases in creatine, NADH, inosine, UDP-galactose, GTP and myoinositol levels in the kidneys of Tsc1cKO mice. Transcriptome analysis revealed 540 mRNAs that were up regulated and 131 mRNAs that were down regulated in Tsc1cKO compared to Wt mice. Enrichment analysis revealed these to belong to pathways associated with collecting duct acid secretion, mTOR signaling, metabolism of amino acids as well as AMPK and AKT signaling.
Conclusion
Metabolome changes point to altered energy production and storage (e.g., Leloir and phosphagen pathways), signal transduction (e.g., lipid signaling) and protein synthesis pathways. The reduced amino acid levels point to their consumption in response to unregulated cell proliferation. This is supported by RNA-seq data which point to an active mTOR signaling pathway. The induction of mTOR signaling is a result of TSC1 deletion in principal cells and a phosphor-inactivation of TSC (experimental data) in genotypically normal A-intercalated cells. Alterations in other metabolites and mRNAs are also indicative of changes in oxidative phosphorylation, protein synthesis, posttranslational modification, proton transport and injury to the cortex in the kidneys of Tsc1cKO mice.
Funding
- Veterans Affairs Support