Nephrin (NPHS1) has been described as an important structural
protein of kidney podocytes. Mutations in this gene lead to the Finnish-type congenital
nephrotic syndrome. More recently, a role of
nephrin as a signalling molecule in kidney podocytes has been identified. Here, we show that
nephrin not only has a function in kidney podocytes, but is also required for cardiovascular development.
Nephrin is expressed in the epicardium and coronary vessels during human and mouse embryonic development.
Nephrin knockout embryos showed abnormal epicardial cell morphology and, at later stages of development, a reduced number of coronary vessels due to increased apoptosis, and in addition, cardiac
fibrosis.
Connexin 43, which is required for coronary vessel formation, was downregulated in
nephrin knockout embryos. Expression of the p75NTR
neurotrophin receptor, a known mediator of apoptosis, was increased in mutants. Furthermore, co-immunoprecipitation studies demonstrated a direct interaction of
nephrin with p75NTR. Primary
nephrin-deficient cardiac cells showed a 5-fold higher rate of apoptosis in response to progenitor of
nerve growth factor compared with wild-type cells, which could be rescued by RNAi against p75NTR. Taken together, our data demonstrate that
nephrin directly interacts with p75NTR and reveal an important role for
nephrin in murine cardiac development by permitting survival of cardiovascular progenitor cells.