Pulmonary Surfactants and the Respiratory-Renal Connection in Steroid Sensitive Nephrotic Syndrome of Childhood

Abstract

Background: Steroid-sensitive nephrotic syndrome (SSNS) in childhood is usually due to minimal change disease (MCD) and unlike many glomerular conditions, it is commonly precipitated by respiratory infections. Of interest, pulmonary inflammation is known to release surfactants in the blood that can bind SIRPα, which is expressed by podocytes and regulates integrin signaling. We performed studies to determine if surfactant-SIRPα interactions may be occurring in MCD. Methods: Studies included developing a novel model of proteinuria by nasal instillation of toll-like receptor ligands (lipopolysaccharide -LPS- and polyinosinic:polycytidylic acid -Poly:IC-), evaluation of serum and urine from 17 children with SSNS/MCD in relapse or remission, and studies using cultured human podocytes treated with sera from children with MCD in remission or relapse. Results: Children with active SSNS/MCD had elevated surfactant proteins A and D in their sera and elevated urinary SIRPα levels, and both decreased when the subjects were in remission. Sera from subjects with SSNS/MCD in relapse, but not in remission, could activate podocyte SIRPα in vitro , leading to release of Src homology 2 domain containing protein tyrosine phosphatase (SHP-2) and Nephrin dephosphorylation thus leading to the activation of the podocyte. The addition of surfactant protein A to MCD sera from a patient in remission could replicate these findings. Similar data was found in mice with nasal instillation of toll-like receptor 4 and 3 agonists LPS and polyI:C which resulted in elevated serum surfactants and their binding to glomeruli triggering proteinuria. Summary: Our data documents a novel pulmonary-podocyte signaling pathway involving surfactants, SIRPα, SHP-2 and Nephrin dephosphorylation in childhood SSNS/MCD.