Abstract: FR-PO172
Mitochondrial Protection Restores Renal Function and Partly Mitigates Cellular Senescence in Swine Atherosclerotic Renal Artery Stenotic Kidney
Session Information
- Mitochondriacs and More
November 03, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Cell Biology
- 202 Apoptosis, Proliferation, Autophagy, Cell Senescence, Cell Transformation
Authors
- Kim, Seo Rin, Mayo Clinic, Rochester, Minnesota, United States
- Zhang, Xin, Mayo Clinic, Rochester, Minnesota, United States
- Eirin, Alfonso, Mayo Clinic, Rochester, Minnesota, United States
- Krier, James, Mayo Clinic, Rochester, Minnesota, United States
- Lerman, Amir, Mayo Clinic, Rochester, Minnesota, United States
- Lerman, Lilach O., Mayo Clinic, Rochester, Minnesota, United States
Background
Atherosclerotic renal artery stenosis (ARAS) may cause kidney injury and mitochondrial dysfunction, which might be linked to cellular senescence. Elamipretide (ELAM), a mitochondrial cardiolipin-targeting peptide, improves renal function and tissue damage in ARAS. We hypothesized that ELAM would also reduce senescence in the ARAS stenotic kidney (STK).
Methods
Domestic pigs were randomized to a 4-week treatment with ELAM (0.1 mg/kg sc q.d.) or vehicle starting after 6 weeks of unilateral ARAS or sham (n=6 each). Then, single kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were measured in-vivo using CT. Renal senescence markers (activity of senescence-associated β-galactosidase (SA-β-Gal), p16, p21, and telomerase reverse transcriptase (TERT)), mitochondrial markers (total cardiolipin content and complex IV (COX-IV) activity), and tissue fibrosis were studied ex-vivo.
Results
Blood pressure and tissue scarring was elevated whereas RBF and GFR were decreased in ARAS STK compared to sham. Renal SA-β-Gal and TERT activity increased in ARAS, suggesting cellular senescence, and total cardiolipin content decreased (Fig. A, B), suggesting mitochondrial impairment. Renal cardiolipin content was restored and COX IV activity was elevated in ELAM-treated ARAS pigs. ELAM also normalized STK-RBF and GFR and improved renal fibrosis in ARAS. ELAM normalized TERT activity, and improved but not normalized SA-β-Gal activity, whereas p16 and p21 gene expression remained unchanged in all groups.
Conclusion
Mitochondrial protection with ELAM improved renal function, fibrosis and mitochondrial dysfunction in the ARAS STK, and partly alleviated cellular senescence. These observations support development of senolytic strategies in ARAS.