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: FR-PO192

Elevated Podocyte DAAM2 Expression in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Qi, Chenyang, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Fogo, Agnes B., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Previously, by using proteomic analysis in isolated glomeruli, we identified several novel differentially expressed proteins in human diabetic nephropathy (DN) vs control, including DAAM2. DAAM2, the dishevelled associated activator of morphogenesis 2 protein, binds the Wnt effector Disheveled, nuclear actin and mediates Wnt-induced cytoskeletal changes. We now aimed to study possible contributions of DAAM2 to DN.

Methods

We assessed DAAM2 by immunostaining in non-cancer regions of human nephrectomy (Nx), DN and normal transplant donor kidney tissues. Nx patients were middle-aged with varying arterionephrosclerosis. ACEI- or glipizide-treated DN mice (db/db/eNOS-/- model) were compared with vehicle-treated DN mice. Primary cultured podocytes were exposed to high glucose or mannitol, and DAAM2 was knocked down by siRNA to study effects on podocyte injury.

Results

In human glomeruli, DAAM2 was expressed only on podocytes. DAAM2 expression was increased in both nephrectomy and DN vs normal donors. DAAM2 gradually decreased with increasing severity of DN, from class II to class III or IV (2.21±0.15 vs 1.58±0.14 vs 1.40±0.14). Glipizide and ACEI reduced DAAM2 podocyte expression in mice DN, accompanied with reduced proteinuria and maintained GFR and more preserved WT1+ podocytes. DAAM2 mRNA was increased in cultured podocytes treated with high glucose vs mannitol (0.36±0.01 vs 0.77±0.03). ROCK1, the downstream kinase of Wnt/Rho/ROCK signaling pathway, regulates podocyte process elongation. High glucose induced more ROCK1 expression than mannitol (1.04±0.04 vs 0.79±0.13), which was reversed by DAAM2 knockdown (0.64±0.07).

Conclusion

DAAM2 is up-regulated in podocytes in both nephrectomy and DN, which we postulate could be contributed to both by glomerular hypertrophy, prevalent in both DN and Nx, and high glucose. We hypothesize that DAAM2 may regulate podocyte function through the Rho/ROCK signaling pathway.

Funding

  • NIDDK Support