The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age

Abstract

Although age-associated changes in kidney glomerular architecture have been described in mice and man, the mechanisms are unknown. It is unclear if these changes can be prevented or even reversed by systemic therapies administered at advanced age. Using light microscopy and transmission electron microscopy, our results showed glomerulosclerosis with injury to mitochondria in glomerular epithelial cells in mice aged 26 month (equivalent to a 79 year old human). To test the hypothesis that reducing mitochondrial damage in late age would result in lowered glomerulosclerosis, we administered the mitochondrial targeted peptide, SS-31 to aged mice. Baseline (24 month-old) mice were randomized to receive 8 weeks of SS-31, or saline, and sacrificed at 26 months of age. SS-31 treatment improved age-related mitochondrial morphology and glomerulosclerosis. Assessment of glomeruli revealed that SS-31 reduced senescence (p16, senescence-associated-β-Gal) and increased the density of parietal epithelial cells. However, SS-31 treatment reduced markers of parietal epithelial cell activation (Collagen IV, pERK1/2 and α-smooth muscle actin). SS-31 did not impact podocyte density, but reduced markers of podocyte injury (desmin), and improved cytoskeletal integrity (synaptopodin). This was accompanied by higher glomerular endothelial cell density (CD31). Thus, despite initiating therapy in late-age mice, a short course of SS-31 has protective benefits on glomerular mitochondria, accompanied by temporal changes to the glomerular architecture. This systemic pharmacological intervention in old-aged animals limits glomerulosclerosis and senescence, reduces parietal epithelial cell activation, and improves podocyte and endothelial cell integrity.

Glutathione peroxidase‐1 overexpression reduces oxidative stress, and improves pathology and proteome remodeling in the kidneys of old mice

“…In addition, the fitted regression for the juxtamedullary cortex showed a coefficient of β 1 = 2.64 and β 2 = −1.49, (both p < .01). A larger β 1 (“slope”) in the juxtamedullary cortex relative to the outer cortex indicated a more prominent change in this region due to aging, consistent with a previous report (Sweetwyne et al., 2017). GPX1 overexpression significantly attenuated glomerular injury, providing ~35% and ~56% protection from changes due to aging in the outer and juxtamedullary cortices, respectively (Figure 2e).…”

“…Taken together, these findings emphasize the roles of ROS, particularly mitochondrial H 2 O 2, in kidney pathology due to aging. Our findings are also consistent with a recent study using SS31 to reverse kidney aging (Sweetwyne et al., 2017). SS31 is a tetra‐peptide that binds to cardiolipin in the inner mitochondrial membrane to improve coupling of oxidative phosphorylation and increase ATP synthesis (Birk et al., 2013; Szeto, 2014).…”

“…Our data from aged mice show increased glomerulosclerosis and compensatory glomerular hypertrophy, tubular atrophy, interstitial fibrosis, and reduced cortical thickness, resembling findings from aged human kidneys. However, in contrast to significant arteriosclerosis observed in humans, we did not find evidence of arteriosclerosis in aged mice, consistent with a prior study (Sweetwyne et al., 2017). This phenotype coincides with reduced severity of other age‐related comorbidities in mice, such as the absence of diabetes and hypertension (Dai et al., 2009).…”

Phase 2a Clinical Trial of Mitochondrial Protection (Elamipretide) During Stent Revascularization in Patients With Atherosclerotic Renal Artery Stenosis

“…Elamipretide (also known as MTP-131 or Bendavia) is a small peptide that targets the mitochondrial matrix independent of membrane potential, preventing peroxidation of cardiolipin 15, 24, 25 . Elamipretide has demonstrated potential for attenuating IRI in experimental models of acute kidney injury (AKI) and improving kidney outcomes and restoring renal function after PTRA in experimental ARAS 13 .…”

Mitochondria Targeted Peptide Attenuates Mitochondrial Dysfunction, Controls Inflammation and Protects Against Spinal Cord Injury-Induced Lung Injury

“…Furthermore, SS-31 can scavenge ROS [18]. In addition, SS-31 is efficacious in reversing mitochondrial dysfunction [17-19].…”