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Abstract: PO2235

Long-Term Mitochondrial Protection Reduces Proteinuria in Obese Aged Mice

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Authors

  • Sweetwyne, Mariya T., University of Washington School of Medicine, Seattle, Washington, United States
  • Coig, Rene, University of Washington School of Medicine, Seattle, Washington, United States
  • Mangalindan, Ruby Sue M., University of Washington School of Medicine, Seattle, Washington, United States
  • Morton, John, University of Washington School of Medicine, Seattle, Washington, United States
  • Whitson, Jeremy A., University of Washington School of Medicine, Seattle, Washington, United States
  • Rabinovitch, Peter S., University of Washington School of Medicine, Seattle, Washington, United States
  • Ladiges, Warren C., University of Washington School of Medicine, Seattle, Washington, United States
Background

In humans, obesity is associated with higher rates of kidney disease, which is compounded by aging. As an energetically demanding tissue, it has been proposed that preventing mitochondrial dysfunction is one key to reducing renal decline. Previously, we showed that an 8-week systemic treatment of aged 24-month-old (m.o.) mice with a mitochondrial targeted protective tetrapeptide, SS-31, significantly reduced the burden of age-induced glomerulosclerosis by 26-m.o. and preserved podocyte integrity.

Methods

To determine if SS-31 aging protection also applied with a comorbidity of obesity, 18-m.o. male NIA C57bl/6j mice were fed regular chow (RC) or a high fat, high sucrose diet (HFHS) for 10 months and treated with SS-31 injected 5x/wk (3 mg/kg) or saline vehicle (n= 20/group).

Results

Mice were weighed weekly. RC mice averaged 33g with no change from age or treatment. HFHS mice gained weight in the first month but by 5 mo. of diet, SS-31+HFHS mice weighed significantly less relative to HFHS untreated mice (40.4g vs. 45.9g p= 0.047).

Spot urine was collected monthly for albumin/creatinine ratio (ACR μg/mg). At 18-m.o. baseline, ACR averaged 48μg/mg. In RC mice, ACR increased modestly, and not significantly, with age although SS-31 RC mice had lower ACR at endpoint (28-m.o. control 125.9 vs. SS-31 60.0). HFHS untreated mice displayed more renal dysfunction by 23 m.o. (ACR: RC = 32.6 vs HFHS = 243.2, p = 0.003), climbing significantly to an average of 519.8 μg/mg at 28-m.o. ACR increased in SS-31 HFHS mice but leveled off by 23-m.o. (5 mo. treat.), averaging 146.1 μg/mg with no significant increase by 28-m.o. By 9 mo. of treatment, ACR was significantly lower in HFHS+SS-31 treated mice.

Preliminary quantification of podocytes by p57 nuclear stain and PAS counter stain (n=4-7) showed that HFHS mice, regardless of treatment, had a 30% decrease in podocyte density relative to RC mice. Control HFHS mice trended to higher tuft volume (glomerular hypertrophy) than in SS-31 HFHS mice. However, results were not significant likely due to small sample size.

Conclusion

Combined with improved ACR our results suggest that podocyte integrity, if not number, may be preserved in mice fed a Western diet by SS-31 intervention and that long-term mitochondrial protection is a potential therapeutic target to preserve renal function with age.

Funding

  • Other NIH Support