TY - JOUR
T1 - Renal ischemia alters expression of mitochondria-related genes and impairs mitochondrial structure and function in swine scattered tubular-like cells
AU - Farahani, Rahele A.
AU - Zhu, Xiang Yang
AU - Tang, Hui
AU - Jordan, Kyra L.
AU - Lerman, Lilach O.
AU - Eirin, Alfonso
N1 - Funding Information:
This work was supported by National Institutes of Health Grants DK106427 (to A. Eirin), DK122137 (to A. Eirin), DK104273 (to L. O. Lerman), DK120292 (to L. O. Lerman), and DK102325 (to L. O. Lerman).
Funding Information:
We thank the Mayo Clinic Genetics, Bioinformatics, and electron Microscopy Cores for technical support for mRNAseq, bioinformatics analysis, and electron microscopy imaging. This work was supported by National Institutes of Health Grants DK106427 (to A. Eirin), DK122137 (to A. Eirin), DK104273 (to L. O. Lerman), DK120292 (to L. O. Lerman), and DK102325 (to L. O. Lerman).
Publisher Copyright:
Copyright © 2020 the American Physiological Society
PY - 2020/7
Y1 - 2020/7
N2 - Farahani RA, Zhu XY, Tang H, Jordan KL, Lerman LO, Eirin A. Renal ischemia alters expression of mitochondria-related genes and impairs mitochondrial structure and function in swine scattered tubular-like cells. Am J Physiol Renal Physiol 319: F19-F28, 2020. First published May 28, 2020; doi:10.1152/ajprenal.00120.2020.-Scattered tubular-like cells (STCs) are dedifferentiated surviving tubular epithelial cells that repair neighboring injured cells. Experimental renal artery stenosis (RAS) impairs STC reparative potency by inducing mitochondrial injury, but the exact mechanisms of mitochondrial damage remain unknown. We hypothesized that RAS alters expression of mitochondria-related genes, contributing to mitochondrial structural damage and dysfunction in swine STCs. CD24+/CD133+ STCs were isolated from pig kidneys after 10 wk of RAS or sham (n = 3 each). mRNA sequencing was performed, and nuclear DNA (nDNA)-encoded mitochondrial genes and mitochondrial DNA (mtDNA)-encoded genes were identified. Mitochondrial structure, ATP generation, biogenesis, and expression of mitochondria-associated microRNAs were also assessed. There were 96 nDNA-encoded mitochondrial genes upregulated and 12 mtDNA-encoded genes downregulated in RAS-STCs versus normal STCs. Functional analysis revealed that nDNA-encoded and mtDNA-encoded differentially expressed genes were primarily implicated in mitochondrial respiration and ATP synthesis. Mitochondria from RAS STCs were swollen and showed cristae remodeling and loss and decreased ATP production. Immunoreactivity of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and expression of the mitochondria-associated microRNAs miR-15a, miR-181a, miR-196a, and miR-296-3p, which target several mtDNA genes, were higher in RAS-STCs compared with normal STCs, suggesting a potential modulation of mitochondria-related gene expression. These results demonstrate that RAS induces an imbalance in mtDNA- and nDNA-mitochondrial gene expression, impairing mitochondrial structure and function in swine STCs. These observations support development of gene gain- and loss-of-function strategies to ameliorate mitochondrial damage and preserve the reparative potency of STCs in patients with renal ischemia.
AB - Farahani RA, Zhu XY, Tang H, Jordan KL, Lerman LO, Eirin A. Renal ischemia alters expression of mitochondria-related genes and impairs mitochondrial structure and function in swine scattered tubular-like cells. Am J Physiol Renal Physiol 319: F19-F28, 2020. First published May 28, 2020; doi:10.1152/ajprenal.00120.2020.-Scattered tubular-like cells (STCs) are dedifferentiated surviving tubular epithelial cells that repair neighboring injured cells. Experimental renal artery stenosis (RAS) impairs STC reparative potency by inducing mitochondrial injury, but the exact mechanisms of mitochondrial damage remain unknown. We hypothesized that RAS alters expression of mitochondria-related genes, contributing to mitochondrial structural damage and dysfunction in swine STCs. CD24+/CD133+ STCs were isolated from pig kidneys after 10 wk of RAS or sham (n = 3 each). mRNA sequencing was performed, and nuclear DNA (nDNA)-encoded mitochondrial genes and mitochondrial DNA (mtDNA)-encoded genes were identified. Mitochondrial structure, ATP generation, biogenesis, and expression of mitochondria-associated microRNAs were also assessed. There were 96 nDNA-encoded mitochondrial genes upregulated and 12 mtDNA-encoded genes downregulated in RAS-STCs versus normal STCs. Functional analysis revealed that nDNA-encoded and mtDNA-encoded differentially expressed genes were primarily implicated in mitochondrial respiration and ATP synthesis. Mitochondria from RAS STCs were swollen and showed cristae remodeling and loss and decreased ATP production. Immunoreactivity of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and expression of the mitochondria-associated microRNAs miR-15a, miR-181a, miR-196a, and miR-296-3p, which target several mtDNA genes, were higher in RAS-STCs compared with normal STCs, suggesting a potential modulation of mitochondria-related gene expression. These results demonstrate that RAS induces an imbalance in mtDNA- and nDNA-mitochondrial gene expression, impairing mitochondrial structure and function in swine STCs. These observations support development of gene gain- and loss-of-function strategies to ameliorate mitochondrial damage and preserve the reparative potency of STCs in patients with renal ischemia.
KW - Mitochondria
KW - Renal artery stenosis
KW - Renovascular disease
KW - Scattered tubular cells
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UR - http://www.scopus.com/inward/citedby.url?scp=85086681960&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00120.2020
DO - 10.1152/ajprenal.00120.2020
M3 - Article
C2 - 32463728
AN - SCOPUS:85086681960
SN - 1970-5557
VL - 319
SP - F19-F28
JO - Oncology Reviews
JF - Oncology Reviews
IS - 1
ER -