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Article

Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome

by
Siting Hong
1,2,†,
Ramyar Ghandriz
1,†,
Sarosh Siddiqi
1,
Xiang-Yang Zhu
1,
Ishran M. Saadiq
1,
Kyra L. Jordan
1,
Hui Tang
1,
Khaled A. Ali
1,
Amir Lerman
3,
Alfonso Eirin
1 and
Lilach O. Lerman
1,*
1
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA
2
Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
3
Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2022, 11(18), 2891; https://doi.org/10.3390/cells11182891
Submission received: 4 August 2022 / Revised: 26 August 2022 / Accepted: 13 September 2022 / Published: 16 September 2022
(This article belongs to the Special Issue Autophagy and Inflammation in Chronic Disease)
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Abstract

Autophagy eliminates excessive nutrients and maintains homeostasis. Obesity and metabolic syndrome (MetS) dysregulate autophagy, possibly partly due to mitochondria injury and inflammation. Elamipretide (ELAM) improves mitochondrial function. We hypothesized that MetS blunts kidney autophagy, which ELAM would restore. Domestic pigs were fed a control or MetS-inducing diet for 16 weeks. During the 4 last weeks, MetS pigs received subcutaneous injections of ELAM (0.1 mg/kg/day, MetS + ELAM) or vehicle (MetS), and kidneys were then harvested to measure protein expression of autophagy mediators and apoptosis. Systemic and renal venous levels of inflammatory cytokines were measured to calculate renal release. The function of isolated mitochondria was assessed by oxidative stress, energy production, and pro-apoptotic activity. MetS slightly downregulated renal expression of autophagy mediators including p62, ATG5-12, mTOR, and AMPK vs. control. Increased mitochondrial H2O2 production accompanied decreased ATP production, elevated apoptosis, and renal fibrosis. In MetS + ELAM, mito-protection restored autophagic protein expression, improved mitochondrial energetics, and blunted renal cytokine release and fibrosis. In vitro, mitoprotection restored mitochondrial membrane potential and reduced oxidative stress in injured proximal tubular epithelial cells. Our study suggests that swine MetS mildly affects renal autophagy, possibly secondary to mitochondrial damage, and may contribute to kidney structural damage in MetS.
Keywords: kidney; metabolic syndrome; autophagy; mitochondria; inflammation kidney; metabolic syndrome; autophagy; mitochondria; inflammation
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MDPI and ACS Style

Hong, S.; Ghandriz, R.; Siddiqi, S.; Zhu, X.-Y.; Saadiq, I.M.; Jordan, K.L.; Tang, H.; Ali, K.A.; Lerman, A.; Eirin, A.; et al. Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome. Cells 2022, 11, 2891. https://doi.org/10.3390/cells11182891

AMA Style

Hong S, Ghandriz R, Siddiqi S, Zhu X-Y, Saadiq IM, Jordan KL, Tang H, Ali KA, Lerman A, Eirin A, et al. Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome. Cells. 2022; 11(18):2891. https://doi.org/10.3390/cells11182891

Chicago/Turabian Style

Hong, Siting, Ramyar Ghandriz, Sarosh Siddiqi, Xiang-Yang Zhu, Ishran M. Saadiq, Kyra L. Jordan, Hui Tang, Khaled A. Ali, Amir Lerman, Alfonso Eirin, and et al. 2022. "Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome" Cells 11, no. 18: 2891. https://doi.org/10.3390/cells11182891

APA Style

Hong, S., Ghandriz, R., Siddiqi, S., Zhu, X.-Y., Saadiq, I. M., Jordan, K. L., Tang, H., Ali, K. A., Lerman, A., Eirin, A., & Lerman, L. O. (2022). Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome. Cells, 11(18), 2891. https://doi.org/10.3390/cells11182891

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