ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

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