Pulmonary surfactants and the respiratory-renal connection in steroid-sensitive nephrotic syndrome of childhood
Gabriel Cara-Fuentes,
Ana Andres-Hernando,
Colin Bauer,
Mindy Banks,
Gabriela E. Garcia,
Christina Cicerchi,
Masanari Kuwabara,
Michiko Shimada,
Richard J. Johnson,
Miguel A. Lanaspa
Affiliations
Gabriel Cara-Fuentes
Division of Pediatric Nephrology, University of Colorado, Aurora, CO, USA
Ana Andres-Hernando
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA; Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA
Colin Bauer
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
Mindy Banks
Rocky Mountain Pediatric Kidney Center, Denver, CO, USA
Gabriela E. Garcia
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
Christina Cicerchi
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
Masanari Kuwabara
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
Michiko Shimada
Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
Richard J. Johnson
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
Miguel A. Lanaspa
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA; Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA; Corresponding author
Summary: Steroid-sensitive nephrotic syndrome (SSNS) in childhood is usually due to minimal change disease (MCD). Unlike many glomerular conditions, SSNS/MCD is commonly precipitated by respiratory infections. Of interest, pulmonary inflammation releases surfactants in circulation which are soluble agonists of SIRPα, a podocyte receptor that regulates integrin signaling. Here, we characterized this pulmonary-renal connection in MCD and performed studies to determine its importance. Children with SSNS/MCD in relapse but not remission had elevated plasma surfactants and urinary SIRPα. Sera from relapsing subjects triggered podocyte SIRPα signaling via tyrosine phosphatase SHP-2 and nephrin dephosphorylation, a marker of podocyte activation. Further, addition of surfactants to MCD sera from patients in remission replicated these findings. Similarly, nasal instillation of toll-like receptor 3 and 4 agonists in mice resulted in elevated serum surfactants and their binding to glomeruli triggering proteinuria. Together, our data document a critical pulmonary-podocyte signaling pathway involving surfactants and SIRPα signaling in SSNS/MCD.
