Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome
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...
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MDPI AG
2022-09-01
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| author | Siting Hong Ramyar Ghandriz Sarosh Siddiqi Xiang-Yang Zhu Ishran M. Saadiq Kyra L. Jordan Hui Tang Khaled A. Ali Amir Lerman Alfonso Eirin Lilach O. Lerman |
| author_facet | Siting Hong Ramyar Ghandriz Sarosh Siddiqi Xiang-Yang Zhu Ishran M. Saadiq Kyra L. Jordan Hui Tang Khaled A. Ali Amir Lerman Alfonso Eirin Lilach O. Lerman |
| author_sort | Siting Hong |
| collection | DOAJ |
| description | 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 H<sub>2</sub>O<sub>2</sub> 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. |
| first_indexed | 2024-03-10T00:25:26Z |
| format | Article |
| id | doaj.art-243b2e4845db4a2e92353998ce5a4901 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T00:25:26Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-243b2e4845db4a2e92353998ce5a49012023-11-23T15:33:58ZengMDPI AGCells2073-44092022-09-011118289110.3390/cells11182891Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic SyndromeSiting Hong0Ramyar Ghandriz1Sarosh Siddiqi2Xiang-Yang Zhu3Ishran M. Saadiq4Kyra L. Jordan5Hui Tang6Khaled A. Ali7Amir Lerman8Alfonso Eirin9Lilach O. Lerman10Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USADepartment of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USAAutophagy 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 H<sub>2</sub>O<sub>2</sub> 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.https://www.mdpi.com/2073-4409/11/18/2891kidneymetabolic syndromeautophagymitochondriainflammation |
| spellingShingle | Siting Hong Ramyar Ghandriz Sarosh Siddiqi Xiang-Yang Zhu Ishran M. Saadiq Kyra L. Jordan Hui Tang Khaled A. Ali Amir Lerman Alfonso Eirin Lilach O. Lerman Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome Cells kidney metabolic syndrome autophagy mitochondria inflammation |
| title | Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome |
| title_full | Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome |
| title_fullStr | Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome |
| title_full_unstemmed | Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome |
| title_short | Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome |
| title_sort | effects of elamipretide on autophagy in renal cells of pigs with metabolic syndrome |
| topic | kidney metabolic syndrome autophagy mitochondria inflammation |
| url | https://www.mdpi.com/2073-4409/11/18/2891 |
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