Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jun;184:45-56.e9.
doi: 10.1016/j.trsl.2017.03.002. Epub 2017 Mar 11.

The Metabolic Syndrome Induces Early Changes in the Swine Renal Medullary Mitochondria

Affiliations
Free PMC article

The Metabolic Syndrome Induces Early Changes in the Swine Renal Medullary Mitochondria

Alfonso Eirin et al. Transl Res. .
Free PMC article

Abstract

The metabolic syndrome (MetS) is associated with nutrient surplus and kidney hyperfiltration, accelerating chronic renal failure. Mitochondria can be overwhelmed by substrate excess, leading to inefficient energy production and thereby tissue hypoxia. Mitochondrial dysfunction is emerging as an important determinant of renal damage, but whether it contributes to MetS-induced renal injury remains unknown. We hypothesized that early MetS induces kidney mitochondrial abnormalities and dysfunction, which would be notable in the vulnerable renal medulla. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with the mitochondria-targeted peptide elamipretide (0.1 mg/kg SC q.d), and Lean controls (n = 7 each). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were measured in-vivo, whereas cortical and medullary mitochondrial structure and function and renal injurious pathways were studied ex-vivo. Blood pressure was slightly elevated in MetS pigs, and their renal blood flow and glomerular filtration rate were elevated. Blood oxygen level-dependent magnetic resonance imaging demonstrated that this was associated with medullary hypoxia, whereas cortical oxygenation remained intact. MetS decreased renal content of the inner mitochondrial membrane cardiolipin, particularly the tetra-linoleoyl (C18:2) cardiolipin species, and altered mitochondrial morphology and function, particularly in the medullary thick ascending limb. MetS also increased renal cytochrome-c-induced apoptosis, oxidative stress, and tubular injury. Chronic mitoprotection restored mitochondrial structure, ATP synthesis, and antioxidant defenses and decreased mitochondrial oxidative stress, medullary hypoxia, and renal injury. These findings implicate medullary mitochondrial damage in renal injury in experimental MetS, and position the mitochondria as a therapeutic target.

Conflict of interest statement

CONFLICT OF INTERESTS

All authors have read the journal’s policy on disclosure of potential conflicts of interest. Dr. A. Lerman is a consultant to Stealth BioTherapeutics, Inc.

Figures

Figure 1
Figure 1
A: Schematic of the experimental protocol. B: Renal cardiolipin content decreased in MetS, but normalized in MetS+ELAM (n=7/group). C: Lyso-cardiolipin content, increased in MetS compared to lean, but decreased in ELAM-treated pigs (n=7/group). D: Renal expression of cardiolipin synthase (CRLS)-1 did not differ among the groups. E: Renal expression of taffazin (Taz)-1 decreased in MetS, but normalized in MetS+ELAM. *p≤0.05 vs. Lean, †p≤0.05 vs. MetS+ELAM.
Figure 2
Figure 2
A: Transmission electron microscopy and quantification of mitochondrial density, mitochondrial area, and matrix density (5 mitochondria/cell) in proximal tubular (PT) and medullary thick ascending limb (mTAL) cells in study groups (n=7/group). B: The ratio of ATP/ADP content in isolated renal cortical and medullary mitochondria decreased in MetS compared to Lean, but normalized in ELAM-treated pigs (n=7/group). C: ELAM decreased medullary mitochondrial hydrogen peroxide (H2O2) production (n=7/group). *p≤0.05 vs. Lean, †p ≤0.05 vs. MetS+ELAM. Scale bar = 200nm.
Figure 3
Figure 3
A: ELAM decreased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end endlabeling (TUNEL)+ and caspase-3+ cells/field in the cortex and medulla (n=7/group). B: Renal protein expression and ratio of B-cell lymphoma (Bcl)-xl and Bcl2-associated X protein (Bax) and Bcl-xl (n=7/group). C: The ratio of mitochondrial/whole tissue cytochrome-c expression decreased in MetS compared to Lean, but normalized in ELAM-treated pigs (n=7/group). D: Lactate dehydrogenase (LDH) levels were elevated in the MetS medulla compared to Lean, but normalized in MetS+ELAM (n=7/group). *p≤0.05 vs. Lean, †p ≤0.05 vs. MetS+ELAM.
Figure 4
Figure 4
A: Representative kidney dihydroethidium (DHE) staining (40X) and its quantification, showing increased renal oxidative stress that ELAM ameliorated (n=7/group). B: Kidney oxidized low-density lipoprotein (ox-LDL) increased in MetS, but normalized in ELAM-treated pigs (n=7/group). C: Representative kidney Periodic acid-Schiff (PAS) staining (40X) and its quantification, showing increased renal tubular injury that ELAM ameliorated (n=7/group). D: Tubulointerstitial fibrosis (trichrome staining) did not differ among the groups (n=7/group). *p ≤0.05 vs. Lean, †p≤0.05 vs. MetS+ELAM. Scale bar = 50μm.

Similar articles

See all similar articles

Cited by 13 articles

See all "Cited by" articles

Publication types

Substances

Feedback