Excess podocyte semaphorin-3A leads to glomerular disease involving plexinA1-nephrin interaction

Kimberly J. Reidy, Pardeep K. Aggarwal, Juan J. Jimenez, David B. Thomas, Delma Veron, Alda Tufro

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Semaphorin-3A (Sema3a), a guidance protein secreted by podocytes, is essential for normal kidney patterning and glomerular filtration barrier development. Here, we report that podocyte-specific Sema3a gain-of-function in adult mice leads to proteinuric glomerular disease involving the three layers of the glomerular filtration barrier. Reversibility of the glomerular phenotype upon removal of the transgene induction provided proof-of-principle of the cause-and-effect relationship between podocyte Sema3a excess and glomerular disease. Mechanistically, excess Sema3a induces dysregulation of nephrin, matrix metalloproteinase 9, and αvβ3 integrin in vivo. Sema3a cell-autonomously disrupts podocyte shape. We identified a novel direct interaction between the Sema3a signaling receptor plexinA1 and nephrin, linking extracellular Sema3a signals to the slit-diaphragm signaling complex. We conclude that Sema3a functions as an extracellular negative regulator of the structure and function of the glomerular filtration barrier in the adult kidney. Our findings demonstrate a crosstalk between Sema3a and nephrin signaling pathways that is functionally relevant both in vivo and in vitro.

Original languageEnglish (US)
Pages (from-to)1156-1168
Number of pages13
JournalAmerican Journal of Pathology
Volume183
Issue number4
DOIs
StatePublished - Oct 2013

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Semaphorin-3A
Podocytes
Glomerular Filtration Barrier
Kidney
nephrin
Matrix Metalloproteinase 9
Diaphragm
Transgenes
Integrins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Excess podocyte semaphorin-3A leads to glomerular disease involving plexinA1-nephrin interaction. / Reidy, Kimberly J.; Aggarwal, Pardeep K.; Jimenez, Juan J.; Thomas, David B.; Veron, Delma; Tufro, Alda.

In: American Journal of Pathology, Vol. 183, No. 4, 10.2013, p. 1156-1168.

Research output: Contribution to journalArticle

Reidy, Kimberly J. ; Aggarwal, Pardeep K. ; Jimenez, Juan J. ; Thomas, David B. ; Veron, Delma ; Tufro, Alda. / Excess podocyte semaphorin-3A leads to glomerular disease involving plexinA1-nephrin interaction. In: American Journal of Pathology. 2013 ; Vol. 183, No. 4. pp. 1156-1168.
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