TY - JOUR
T1 - Excess podocyte semaphorin-3A leads to glomerular disease involving plexinA1-nephrin interaction
AU - Reidy, Kimberly J.
AU - Aggarwal, Pardeep K.
AU - Jimenez, Juan J.
AU - Thomas, David B.
AU - Veron, Delma
AU - Tufro, Alda
N1 - Funding Information:
Supported by NIH grants R01-DK64187 (A.T.), R01-DK59333 (A.T.), and T32-DK007110 (K.R.) and a grant from the Emerald Foundation (A.T.).
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2013.06.022
DO - 10.1016/j.ajpath.2013.06.022
M3 - Article
C2 - 23954273
AN - SCOPUS:84884549522
SN - 0002-9440
VL - 183
SP - 1156
EP - 1168
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -