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A previously unrecognized role of C3a in proteinuric progressive nephropathy

Marina Morigi1, Monica Locatelli1, Cinzia Rota1

  • 1IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.

Scientific Reports
|June 28, 2016
PubMed

Insights

Uncontrolled complement alternative pathway (AP) activation drives podocyte loss and parietal epithelial cell (PEC) activation, leading to glomerulosclerosis in proteinuric kidney diseases.

Area of Science:

  • Nephrology
  • Immunology
  • Pathology

Background:

  • Podocyte loss initiates glomerulosclerosis, a key feature of proteinuric nephropathies.
  • Understanding glomerular injury mechanisms is crucial for developing new therapeutic targets.

Purpose of the Study:

  • To investigate if the complement alternative pathway (AP) mediates podocyte depletion and parietal epithelial cell (PEC) activation in protein-overload-induced glomerulosclerosis.
  • To explore the role of C3a, CXCR4, and GDNF/c-Ret signaling in this process.

Main Methods:

  • Utilized mice deficient in Factor H or Factor B, alongside wild-type littermates, subjected to bovine serum albumin (BSA)-induced protein overload.
  • Conducted in vitro studies using PECs and analyzed patient samples from proteinuric nephropathy cases.

Main Results:

  • BSA-induced protein overload caused podocyte depletion, PEC activation, and glomerulosclerosis in wild-type mice, exacerbated in Factor H-deficient mice.
  • Factor B deficiency protected against glomerular injury, confirming the pathogenic role of the AP.
  • Complement component C3a directly promoted PEC proliferation and migration, an effect amplified by podocyte-derived GDNF via the c-Ret axis.
  • Glomerular C3/C3a, PEC activation, CXCR4, and GDNF were upregulated in both mouse models and human proteinuric nephropathy patients.

Conclusions:

  • Uncontrolled activation of the complement alternative pathway is essential for podocyte-dependent PEC activation and subsequent glomerulosclerosis.
  • Targeting the AP, C3a, or the GDNF/c-Ret/CXCR4 axis may offer novel therapeutic strategies for proteinuric kidney diseases.

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