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Semaphorin3a Promotes Advanced Diabetic Nephropathy

Publication ,  Journal Article
Aggarwal, PK; Veron, D; Thomas, DB; Siegel, D; Moeckel, G; Kashgarian, M; Tufro, A
Published in: Diabetes
May 1, 2015

The onset of diabetic nephropathy (DN) is highlighted by glomerular filtration barrier abnormalities. Identifying pathogenic factors and targetable pathways driving DN is crucial to developing novel therapies and improving the disease outcome. Semaphorin3a (sema3a) is a guidance protein secreted by podocytes. Excess sema3a disrupts the glomerular filtration barrier. Here, using immunohistochemistry, we show increased podocyte SEMA3A in renal biopsies from patients with advanced DN. Using inducible, podocyte-specific Sema3a gain-of-function (Sema3a+) mice made diabetic with streptozotocin, we demonstrate that sema3a is pathogenic in DN. Diabetic Sema3a+ mice develop massive proteinuria, renal insufficiency, and extensive nodular glomerulosclerosis, mimicking advanced DN in humans. In diabetic mice, Sema3a+ exacerbates laminin and collagen IV accumulation in Kimmelstiel-Wilson-like glomerular nodules and causes diffuse podocyte foot process effacement and F-actin collapse via nephrin, αvβ3 integrin, and MICAL1 interactions with plexinA1. MICAL1 knockdown and sema3a inhibition render podocytes not susceptible to sema3a-induced shape changes, indicating that MICAL1 mediates sema3a-induced podocyte F-actin collapse. Moreover, sema3a binding inhibition or podocyte-specific plexinA1 deletion markedly ameliorates albuminuria and abrogates renal insufficiency and the diabetic nodular glomerulosclerosis phenotype of diabetic Sema3a+ mice. Collectively, these findings indicate that excess sema3a promotes severe diabetic nephropathy and identifies novel potential therapeutic targets for DN.

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Published In

Diabetes

DOI

EISSN

1939-327X

ISSN

0012-1797

Publication Date

May 1, 2015

Volume

64

Issue

5

Start / End Page

1743 / 1759

Publisher

American Diabetes Association

Related Subject Headings

  • Endocrinology & Metabolism
  • 11 Medical and Health Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Aggarwal, P. K., Veron, D., Thomas, D. B., Siegel, D., Moeckel, G., Kashgarian, M., & Tufro, A. (2015). Semaphorin3a Promotes Advanced Diabetic Nephropathy. Diabetes, 64(5), 1743–1759. https://doi.org/10.2337/db14-0719
Aggarwal, Pardeep K., Delma Veron, David B. Thomas, Dionicio Siegel, Gilbert Moeckel, Michael Kashgarian, and Alda Tufro. “Semaphorin3a Promotes Advanced Diabetic Nephropathy.” Diabetes 64, no. 5 (May 1, 2015): 1743–59. https://doi.org/10.2337/db14-0719.
Aggarwal PK, Veron D, Thomas DB, Siegel D, Moeckel G, Kashgarian M, et al. Semaphorin3a Promotes Advanced Diabetic Nephropathy. Diabetes. 2015 May 1;64(5):1743–59.
Aggarwal, Pardeep K., et al. “Semaphorin3a Promotes Advanced Diabetic Nephropathy.” Diabetes, vol. 64, no. 5, American Diabetes Association, May 2015, pp. 1743–59. Crossref, doi:10.2337/db14-0719.
Aggarwal PK, Veron D, Thomas DB, Siegel D, Moeckel G, Kashgarian M, Tufro A. Semaphorin3a Promotes Advanced Diabetic Nephropathy. Diabetes. American Diabetes Association; 2015 May 1;64(5):1743–1759.

Published In

Diabetes

DOI

EISSN

1939-327X

ISSN

0012-1797

Publication Date

May 1, 2015

Volume

64

Issue

5

Start / End Page

1743 / 1759

Publisher

American Diabetes Association

Related Subject Headings

  • Endocrinology & Metabolism
  • 11 Medical and Health Sciences