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Abstract: PO1695

ACE Inhibition Modulates Insulin-Like Growth Factor 1 (IGF-1) Filtration to Regulate Compensatory Kidney and Glomerular Hypertrophy

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Naik, Abhijit S., University of Michigan, Ann Arbor, Michigan, United States
  • Wang, Su Qing, University of Michigan, Ann Arbor, Michigan, United States
  • Chowdhury, Mahboob A., University of Michigan, Ann Arbor, Michigan, United States
  • Menon, Rajasree, University of Michigan, Ann Arbor, Michigan, United States
  • Otto, Edgar A., University of Michigan, Ann Arbor, Michigan, United States
  • Wiggins, Jocelyn E., University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Bitzer, Markus, University of Michigan, Ann Arbor, Michigan, United States
  • Wiggins, Roger C., University of Michigan, Ann Arbor, Michigan, United States
Background

Modeling suggests that preventing glomerular volume (GV) increase could serve as a therapeutic target to mitigate hypertrophy-associated progressive glomerulosclerosis (GS). We, therefore, evaluated how GV is regulated, and how Angiotensin-Converting Enzyme inhibition (ACEi) could reduce compensatory GV increase.

Methods

Uni-nephrectomized (Uni-Nx) wild-type Fischer344 rats were used to model progressive GS triggered by the single kidney state, and the effect of ACEi started either before or after Uni-Nx. Urine IGF ELISA assay, computer-assisted morphometry, single-cell, bulk transcriptomics, immunofluorescence, and human databases were analyzed.

Results

ACEi started before, but not after Uni-Nx, reduced short (Panel A) and long-term (Panel B) compensatory GV increase, and the associated 8-fold peak of urine IGF-1 post-nephrectomy (Panel C). An IGF-1R inhibitor (picropodophyllin) also reduced compensatory kidney hypertrophy (Panel D). Post-Uni-Nx, a decrease in both serum IGF-1 and glomerular/kidney IGF-1 transcript were noted, and IGFBP3 (the major blood IGFBP) was present in podocyte cytoplasm in the absence of detectable podocyte IGFBP3 transcript, suggesting that IGF-1 and IGF-IGFBP3 complexes had come from blood. A model was developed to predict how IGF-1, IGF-2, and IGF-IGFBP protein complexes would interact with the glomerular filter, and its predictions were confirmed in ERCB database. The importance of hyperfiltered IGF-1 as a driver of glomerular failure in single kidney states was further supported by human kidney allograft half-life analysis.

Conclusion

Hyperfiltered IGF-1 drives compensatory GV increase leading to long-term proteinuria and GS. Timing of ACEi in relation to uni-Nx can reduce both IGF-1 hyperfiltration and GV increase, thereby prolonging single kidney lifespan.

Funding

  • NIDDK Support