SS-31  & Kidney Health Research Overview

SS-31 (also known as elamipretide) is a mitochondria-targeted tetrapeptide that has drawn intense interest in kidney health research. By selectively localizing to the inner mitochondrial membrane and interacting with cardiolipin, SS-31 peptide appears to stabilize mitochondrial structure, reduce reactive oxygen species, and support ATP generation during stress. Rodent models of acute kidney injury and ischemia-reperfusion, as well as early human studies with renal endpoints, have made SS-31 a central tool compound for renal mitochondrial research.

This page is a research-focused overview only. All peptides mentioned here—including SS-31, GLP3-R, SLU-PP-332, AOD 9604 and IGF-1 LR3—are research compounds, not approved drugs, and are not intended for human or veterinary use.

SS-31 peptide kidney mitochondria research illustration

SS-31 Peptide: Mitochondrial Mechanism in Kidney Cells

SS-31 is a small, cationic, aromatic tetrapeptide that carries a strong positive charge, enabling it to accumulate in the negatively charged inner mitochondrial membrane. There, it binds to cardiolipin, a phospholipid critical for maintaining cristae architecture and electron transport chain supercomplexes. In renal ischemia-reperfusion models, SS-31 appears to:

  • Preserve mitochondrial cristae structure and respiratory chain function
  • Reduce mitochondrial ROS production during reperfusion
  • Accelerate recovery of ATP levels after ischemic insult
  • Attenuate opening of the mitochondrial permeability transition pore (mPTP)

Work in rats and mice has shown that these mitochondrial effects translate into less tubular cell apoptosis and necrosis, improved tubular function, and reduced histologic evidence of acute kidney injury after ischemia-reperfusion episodes.1–3 A genome-wide CRISPR screen in kidney-derived cells further suggested that SS-31 may signal through PLSCR3 phospholipid scramblase, adding nuance to earlier models focused purely on antioxidant effects.4

Rodent Studies: SS-31 in Acute and Chronic Kidney Injury

Several lines of rodent research have converged on the idea that SS-31 can modulate both acute injury and longer-term progression to chronic kidney disease (CKD):

Ischemia-Reperfusion (IR) Models

In classic renal IR models, transient clamping of the renal artery is used to mimic surgical or hemodynamic ischemia. Administration of SS-31 in these models has been associated with:

  • Protection of mitochondrial structure and respiration during early reperfusion
  • Faster ATP recovery in kidney tissue
  • Reduction in tubular necrosis and apoptosis on histology
  • Improved serum creatinine and BUN profiles during the recovery phase

A 2022 review of oxidative stress in kidney ischemia highlighted SS-31 as one of the better-characterized mitochondria-targeted peptides in this context, emphasizing its effects on cardiolipin integrity, ROS reduction, and tubular cell survival.1,3

Toxic Nephropathy and Glomerular Injury

Separate murine models using aristolochic acid and adriamycin to induce tubular and glomerular damage have shown that SS-31 can reduce markers of acute kidney injury and modulate inflammatory and oxidative-stress pathways. In these models, SS-31 treatment:

  • Dampened expression of genes involved in acute inflammatory responses and oxidative damage
  • Improved histologic measures of both tubulointerstitial and glomerular injury
  • Influenced the renal renin-angiotensin system (RAS), including normalization of aminopeptidase A and a shift in AT1R/AT2R expression balance

These data support the concept that SS-31’s benefits extend beyond simple free-radical scavenging, touching upstream regulators of vascular tone and fibrosis relevant to kidney disease progression.2,5

Preventing CKD Progression after AKI

A long-term rat study subjected animals to bilateral renal ischemia and then followed them for nine months. Even when administered after the acute insult, SS-31 limited the transition from acute injury to chronic kidney disease, with treated rats demonstrating:

  • Lower glomerulosclerosis and interstitial fibrosis scores
  • Better preservation of GFR-equivalent measures
  • Improved mitochondrial markers in renal tissue

This work strengthened the hypothesis that preserving mitochondrial function early after injury can have durable effects on CKD risk and progression.3

 

 

 

Human Studies with Renal Endpoints: Early but Encouraging

While most SS-31 kidney data are preclinical, elamipretide has reached phase 2 and 3 clinical trials in other indications, providing human safety and organ-specific signals. A notable kidney-focused pilot trial evaluated adjunctive elamipretide during percutaneous transluminal renal angioplasty (PTRA) for atherosclerotic renal artery stenosis.

  • Patients undergoing renal artery stenting were randomized to elamipretide or placebo.
  • At three months, the elamipretide group showed higher cortical perfusion, increased renal blood flow, and a greater rise in eGFR compared with placebo.
  • The treatment was generally well tolerated, supporting the feasibility of peri-procedural mitochondrial protection strategies in humans.6,7

Separate cardiorenal trials (e.g., NCT02914665) have examined short-term elamipretide administration in heart-failure populations, tracking cardiac and renal endpoints. Although these studies are heterogeneous in design and not all primary endpoints have been met, they collectively suggest:

  • A favorable safety profile over weeks to months of dosing
  • Signals of improved renal perfusion or biomarkers in some subgroups
  • Clear evidence that kidney outcomes can be integrated into elamipretide trial designs without prohibitive safety concerns6,8,9

Importantly, phase 3 work in primary mitochondrial myopathy (MMPOWER-3) did not show benefit on its primary functional endpoint (6-minute walk test) despite acceptable tolerability, emphasizing that promising mechanistic and organ-level data do not guarantee clinical efficacy.9

Positioning SS-31 Next to GLP3-R, SLU-PP-332, AOD 9604 and IGF-1 LR3

In many experimental programs, SS-31 is not studied in isolation. Instead, it sits alongside endocrine and metabolic tools that affect kidney health indirectly by modulating systemic risk factors:

  • GLP3-R 20mg and GLP3-R 10mg (GLP3-Reta-style triple agonists) are used to explore incretin-based effects on weight, insulin sensitivity, and blood pressure—all major determinants of long-term renal risk.
  • SLU-PP-332 is a pan-ERR agonist and exercise-mimetic compound that upregulates oxidative metabolism and may influence renal energetics secondarily through systemic metabolic changes.
  • AOD 9604 is a growth hormone fragment peptide studied for lipolytic effects and body-composition changes in rodent and limited human studies, making it a body-fat and metabolic comparator in renal-metabolic research.
  • IGF-1 LR3 (often requested as “IGF-1 LR4” but typically supplied as LR3) is used to interrogate IGF1R-driven anabolic and metabolic signaling, including potential effects on glomerular and tubular cells.

By combining mitochondrial-targeted SS-31 with systemic metabolic tools like GLP3-R, SLU-PP-332, AOD 9604 or IGF-1 LR3 in parallel arms (not necessarily stacked), investigators can ask whether renal outcomes track more closely with intrinsic mitochondrial protection, with endocrine/metabolic remodeling, or with both.

 

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This reinforces SS-31, GLP3-R, SLU-PP-332, AOD 9604 and IGF-1 LR3 as part of a coherent research content cluster.

Limitations, Safety Framing & Research-Only Context

Despite compelling preclinical data and promising signals in early human renal studies, several limitations remain:

  • Most kidney outcomes for SS-31 derive from rodent models, which may not fully replicate human disease complexity.
  • Human trials are relatively small, with heterogeneous populations and endpoints, and key phase 3 results in other indications have been mixed.
  • Long-term safety and efficacy of chronic mitochondrial modulation in the kidney remain open questions.

For these reasons, SS-31, GLP3-R, SLU-PP-332, AOD 9604 and IGF-1 LR3 are appropriately confined to laboratory and in-vitro research use. All handling must adhere to local regulations and institutional policies, and nothing in this article should be interpreted as medical advice or endorsement of off-label or non-research use.

Within that framework, SS-31 peptide offers a powerful lens into how mitochondria shape renal resilience and vulnerability, while related endocrine and metabolic tools help map the broader landscape of kidney health in the context of systemic metabolism.