Table 1.

Activating factors and molecular pathways underlying tubular epithelial cell dysfunction and interstitial inflammation and fibrosis in progressive proteinuric nephropathiesa

Transcription factor–mediated upregulation of inflammatory, vasoactive, and fibrogenic genes in proximal tubular cells by protein overload
    NF-κB–dependent pathways for synthesis and polarize secretion of MCP-1, RANTES, IL-8, fractalkine, ET-1(1618,24,25)
    STAT activation(30)
    TGF-β upregulation(19,96)
Activation of the complement cascade in proximal tubule
    upregulation and basolateral/apical secretion of C3 by proximal tubular cells in response to plasma protein overload(20)
    deposition of C3 (newly synthesized, ultrafiltered) on apical surface; activation viaalternative pathway(71,72,75,83)
    C5b-9–mediated upregulation of extracellular matrix proteins (collagen IV, fibronectin)(74,76)
    C3a receptor–mediated TGF-β and collagen synthesis(52)
    interaction of C3 with ammonium generated as a result of excess protein degradation leading to formation of monocyte-activating products(109)
Tubular cell activation by protein-bound circulating molecules
    release of albumin-bound chemoattractant lipid factor(34)
    IGF-1, HGF, and TGF-β receptor–mediated synthesis of collagen type I and IV, MCP-1, RANTES(97)
Apoptotic response to protein overload
    activation of Fas pathways in proximal and distal tubular cells(105,106)
    PPAR-γ–mediated proximal tubular cell apoptosis(102)
  • a ET-1, endothelin-1; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor 1; MCP-1, monocyte chemoattractant protein-1; PPAR-γ, peroxisome proliferator–activated receptor-γ; STAT, signal transducer and activator of transcription.