Table 1.

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

Factor/PathwayReferences
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.