Abstract: FR-PO146

ABCA1 Mediated Mitochondrial Remodeling in Podocyte Injury and Diabetic Kidney Disease

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1003 Glomerular: Cell Biology

Authors

  • Ducasa, Gloria Michelle, Univ of Miami, Miami, Florida, United States
  • Fornoni, Alessia, Univ of Miami, Miami, Florida, United States
  • Sloan, Alexis J., Univ of Miami, Miami, Florida, United States
  • Pedigo, Christopher E., Univ of Miami, Miami, Florida, United States
  • Correa, Mayrin, Univ of Miami, Miami, Florida, United States
  • Kretzler, Matthias, U.Michigan, Ann Arbor, Michigan, United States
  • Mendez, Armando, Univ of Miami, Miami, Florida, United States
  • Nelson, Robert G., NIDDK, Phoenix, Arizona, United States
  • Fontanesi, Flavia, Univ of Miami, Miami, Florida, United States
  • Merscher, Sandra M., Univ of Miami, Miami, Florida, United States
Background

Diabetic kidney disease (DKD) is the most common cause of ESKD. Decreased podocyte number and glomerular lipid accumulation occurs in clinical and experimental DKD. It has been suggested that podocyte injury in DKD may result from impaired ATP Binding Cassette A1 (ABCA1) mediated cholesterol efflux, mitochondrial dysfunction or increased reactive oxygen species (ROS). However, if impaired ABCA1 function confers susceptibility to DKD by contributing to mitochondrial dysfunction or ROS remains to be established.

Methods

Patients enrolled in the “Renoprotection in Early Diabetic Nephropathy in Pima Indians trial” were separated into progressors and non-progressors (dGFR -97.39±8.2,n=15 and +40.62±8.6, n=16, respectively) based on the change in glomerular filtration rate (dGFR) between enrollment and last examination (10±1.7 years). Human podocytes were treated with patient sera. ABCA1 expression and cholesterol efflux were measured. SiRNA ABCA1 (siABCA1p) and scrambled control (siCO) podocytes were treated with progressor sera and analyzed for caspase 3 activity. Mitochondrial respiratory chain complexes and ROS production were measured in siABCA1p. Podocyte specific Abca1 fl/fl mice were injected with streptozotocin (STZ) or bred to BTBR ob/ob (DKO) mice. Proteinuria was measured.

Results

Podocytes treated with progressor sera showed reduced ABCA1 mRNA expression (p<0.05) and cholesterol efflux (p<0.01) compared to non-progressors. siABCA1p treated with progressor sera have increased caspase 3 activity (p<0.05) compared to siCO. siABCA1p have increased mitochondrial respirasome formation (p<0.01), complex I activity (p<0.05) and ROS production (p<0.001). STZ injected Abca1 fl/fl (p<0.05) and DKO mice (p<0.01) have increased albuminuria compared to diabetic controls.

Conclusion

Our in vitro and in vivo studies show that reduced ABCA1 expression confers susceptibility to DKD progression possibly by contributing to mitochondrial remodeling. Treatment strategies aimed at restoring ABCA1 function or mitochondrial dysfunction may be beneficial to prevent podocyte injury in DKD.

Funding

  • NIDDK Support