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Abstract: TH-PO870

ABCA1 Mediated Mitochondrial Dysfunction Contributes to Podocyte Injury in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ducasa, Gloria Michelle, University of Miami School of Medicine/Katz Division of Nephrology, Miami, Florida, United States
  • Mitrofanova, Alla, University of Miami School of Medicine/Katz Division of Nephrology, Miami, Florida, United States
  • Pedigo, Christopher E., Yale University, New Haven, Connecticut, United States
  • Sloan, Alexis J., University of Miami School of Medicine/Katz Division of Nephrology, Miami, Florida, United States
  • Kretzler, Matthias, U.Michigan, Ann Arbor, Michigan, United States
  • Ishimoto, Yu, Tokyo University, Hongo, TOKYO, Japan
  • Inagi, Reiko, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, TOKYO, Japan
  • Mendez, Armando, University of Miami, Miami, Florida, United States
  • Nelson, Robert G., National Institutes of Health, Phoenix, Arizona, United States
  • Burke, George William, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Fontanesi, Flavia, University of Miami, Miami, Florida, United States
  • Merscher, Sandra M., University of Miami School of Medicine/Katz Division of Nephrology, Miami, Florida, United States
  • Fornoni, Alessia, University of Miami School of Medicine/Katz Division of Nephrology, Miami, Florida, United States
Background

Diabetic kidney disease (DKD) is characterized by podocyte loss, altered mitochondrial oxidative phosphorylation complexes (OXPHOS), and glomerular lipid accumulation. We have shown that ATP Binding Cassette A1 (ABCA1)-mediated cholesterol efflux is impaired in clinical and experimental DKD. Here, we test the hypothesis that ABCA1 deficiency causes mitochondrial dysfunction in podocytes and contributes to injury in DKD.

Methods

Sera were obtained from Pima Indian patients with diabetes and progressive DKD (P, n=15) and non-progressive DKD (NP, n=16) as assessed by changes in measured GFR over a 10 year period. Scrambled control (siCO) and siRNA ABCA1 podocytes (siABCA1p) were treated with patient sera. ABCA1 expression, cholesterol efflux, mitochondrial OXPHOS complexes, cardiolipin (mitochondrial specific phospholipid) content and cytotoxicity were measured. Elamipretide (cardiolipin peroxidase inhibitor) was utilized for selected in vitro and in vivo experiments. BTBRob/ob (ob/ob) mice with podocyte specific ABCA1 deficiency (DKO) were generated and analyzed.

Results

P sera treated podocytes show reduced ABCA1 mRNA expression, and cholesterol efflux and increased cytotoxicity compared to NP. siABCA1p are more susceptible to NP and P sera induced cytotoxicity when compared to siCO. siABCA1p show decreased basal OCR, cardiolipin accumulation, and alterations in OXPHOS complexes. Elamipretide treated siABCA1p are protected from NP and P sera mediated cytotoxicity compared to siCO. DKO mice have increased albuminuria, mesangial expansion, podocyte loss, FPE and mitochondrial damage as compared to ob/ob mice. Treatment with Elamipretide of db/db mice is sufficient to reduce albuminuria, mesangial expansion, BUN and podocyte loss.

Conclusion

Our data indicate that a reduction of ABCA1 expression in podocytes is a susceptibility factor for DKD progression. These data also indicate that ABCA1 deficiency results in cardiolipin accumulation and mitochondrial dysfunction. Inhibition of cardiolipin oxidation prevents podocyte loss and DKD in diabetic mice. Treatment strategies to restore ABCA1 function may be beneficial in DKD.

Funding

  • NIDDK Support