Kidney Week

Abstract: SA-OR022

Selective Deletion of EGFR in Podocytes Protects against Nephropathy in Type II Diabetes

Session Information

• Diabetic Kidney Disease: Mechanisms, Models, and Modulators - II
  October 27, 2018 | Location: 5A, San Diego Convention Center
  Abstract Time: 04:42 PM - 04:54 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Li, Yan, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Yan Li

• Sasaki, Kensuke, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Kensuke Sasaki,

• Wang, Yinqiu, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Yinqiu Wang,

• Niu, Aolei, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Aolei Niu,

• Wang, Suwan, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Suwan Wang,

• Fan, Xiaofeng, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Xiaofeng Fan,

• Chen, Jianchun, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Jianchun Chen,

• Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ming-Zhi Zhang,

• Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Raymond C. Harris,

Background

Previous studies by us and others have indicated that renal epidermal growth factor receptor (EGFR) signaling is activated in DN and EGFR inhibition protects against DN. In the present study, we examined whether selective EGFR deletion in podocytes affected development of DN in type II diabetes.

Methods

db/db mice with selective podocyte EGFR deletion (podocin-Cre; EGFR^f/f; db/db: EGFR^podKO;db/db) and an accelerated type II diabetic model (eNOS^-/-; db/db mice) with selective podocyte EGFR deletion (podocin-Cre; EGFR^f/f; eNOS^-/-; db/db: EGFR^podKO; eNOS^-/-; db/db) were generated and used. Genotypes were confirmed before sacrifice. A mouse podocyte cell line was used for in vitro studies.

Results

Selective podocyte EGFR deletion was confirmed by reduced EGFR co-IF with WT1. Podocyte EGFR deletion had no effect on body weight and fasting blood sugar in either db/db or eNOS^-/-; db/db mice. However, podocyte EGFR deletion led to marked reduction in albuminuria in both db/db and eNOS^-/-; db/db mice [albumin vs. creatinine ratio (µg/mg): 175 ± 11 vs. 495 ± 16 in 40 week old db/db , P < 0.01; 2185 ± 175 vs. 3434 ± 418 in 20 week old eNOS^-/-; db/db mice, P < 0.05]. Glomerulosclerosis index was lower in EGFR^podKO; eNOS^-/-; db/db mice than in eNOS^-/-; db/db mice at 20 weeks. In eNOS^-/-; db/db mice, podocyte EGFR deletion produced less podocyte loss, as indicated by increased mRNA levels of podocin and higher podocyte number per glomerulus section (10.7 ± 0.5 vs. 7.0 ± 0.2, P < 0.001), in association with decreases in proinflammatory cytokine/chemokine levels, including iNOS, IRF5, IL-23, IL-1α, IL-1β, CCL-3, TNF-α and IL-6 as well as pro-fibrotic and fibrotic components, TGF-β1 and collagen I and IV. Both in vivo and in cultured podocytes exposed to high glucose, inhibition of podocyte EGFR signaling suppressed the mTOR/p70 S6K signaling pathway, leading to stimulation of a podocyte protective autophagic pathway, as indicated by increased beclin 1 and decreased rubicon, an inhibitor of beclin 1, and decreases in the autophagic substrate, p62.

Conclusion

These studies indicate that activation of a podocyte EGFR signaling pathway contributes to progression of diabetic nephropathy, at least in part due to activation of an EGFR/mTOR/p70 S6K pathway, leading to inhibition of podocyte autophagy and subsequent cell injury.

Funding

• NIDDK Support