Semaphorin3a promotes advanced diabetic nephropathy.

Abstract

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.

• Authors: Pardeep K Aggarwal, Delma Veron, David B Thomas, Dionicio Siegel, Gilbert Moeckel, Michael Kashgarian, Alda Tufro
• Journal: Diabetes (Diabetes) Vol. 64 Issue 5 Pg. 1743-59 (May 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 25475434 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Actins
• Chromones
• Collagen Type IV
• Integrin alphaVbeta3
• Laminin
• Membrane Proteins
• Microfilament Proteins
• Microtubule-Associated Proteins
• Nerve Tissue Proteins
• Plxna1 protein, mouse
• Receptors, Cell Surface
• Semaphorin-3A
• WT1 Proteins
• Xanthones
• nephrin
• xanthofulvin
• Mical1 protein, mouse
• Mixed Function Oxygenases

Topics

• Actins (metabolism)
• Animals
• Chromones
• Collagen Type IV (genetics, metabolism)
• Diabetes Mellitus, Experimental
• Diabetic Nephropathies (metabolism, pathology)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation
• Gene Knockdown Techniques
• Humans
• Integrin alphaVbeta3 (genetics, metabolism)
• Laminin (genetics, metabolism)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Microfilament Proteins
• Microtubule-Associated Proteins (genetics, metabolism)
• Mixed Function Oxygenases (genetics, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Podocytes (metabolism)
• Proteinuria (etiology)
• Receptors, Cell Surface (genetics, metabolism)
• Renal Insufficiency
• Semaphorin-3A (blood, genetics, metabolism, urine)
• WT1 Proteins (genetics, metabolism)
• Xanthones