Abstract: TH-PO074

Novel Role for Podocyte SIRPα and Pulmonary Surfactants in Minimal Change Disease

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Lanaspa, Miguel A., University of Colorado Denver, Aurora, Colorado, United States
  • Andres-hernando, Ana, University of Colorado Denver, Aurora, Colorado, United States
  • Cicerchi, Christina, University of Colorado Denver, Aurora, Colorado, United States
  • Johnson, Richard J., University of Colorado Denver, Aurora, Colorado, United States
Background

Minimal change disease (MCD) is the most common cause of proteinuria and nephrotic syndrome in children whose primary cause is unknown. Recent studies identified podocyte CD80 as a key deleterious player in MCD. SIRPα is a receptor that regulates cell growth and differentiation by controlling phosphatases like PTPN11. SIRPα agonists include soluble surfactants SP-A and SP-D, produced by an anti-inflammatory response in the lungs. Here, we propose that MCD is associated with the elevation of serum SP-A and SP-D. that stimulate podocyte SIRPα to activate a signaling cascade mediated by PTPN11, nephrin dephosphorylation, CD80 expression and actin reorganization causing the activation of the podocye, loss of foot processes, proteinuria and nephrotic syndrome.

Methods

Serum, renal and urinary levels of surfactants are determined in MCD subjects in relapse and remission and correlated with albumin excretion and urinary CD80. To test the role of surfactants in podocyte activation, podocytes are exposed to serum from patients in relapse or in remission in which surfactants are added back and SIRPα, PTPN11 activity, nephrin phosphorylation, CD80 expression, actin re-organization and proteinuria is determined in these podocytes and in a mouse model of intranasal exposure to LPS.

Results

Human subjects with MCD in relapse but not remission and intranasal exposure to LPS in mice have elevated serum SP-A/D suggesting a crosstalk between lungs and kidneys. The stimulation of SIRPα in cultured podcytes with serum from MCD patients in relapse or by addition back of surfactants to serum of patients in remission releases PTPN11 from SIRPα to interact and dephosphorylate nephrin. This action results in NfkB activation and transcription of CD80 and pro-inflammatory cytokines, Similarly, nephrin loss results in loss of cell polarity that combined with the pro-inflammatory response re-organizes actin structure leading to the podocyte activation

Conclusion

Based on our data and the observation that 70% of the cases of MCD relapses are preceded by respiratory tract infections, we conclude that MCD is associated with the deregulation of podocyte SIRPα signaling leading to its activation characterized by PTPN11-mediated nephrin dephosphorylation, CD80 expression and actin reorganization ultimately causing loss of foot processes, proteinuria and nephrotic syndrome.

Funding

  • NIDDK Support