Table 2 Signalling pathways activated by MAC (adapted from Takano et al. (2013). Seminars in Nephrology. Reference [52]
From: New insights into the immune functions of podocytes: the role of complement
Pathway | Effects of terminal pathway activation |
|---|---|
Intracellular calcium | Calcium influx through MAC and calcium release from intracellular storage sites |
Protein kinases | Activation of protein kinase C (PKC), receptor tyrosine kinase (RTK), Ras-ERK, JNK, p38, and ASK1 (HN) |
Phospholipases | Activation of phospholipase C (PLC)-γ1, cPLA2, and iPLA2-γ (phosphorylation), and AA release |
Prostanoids | Upregulation of cyclooxygenase (COX)-2 (cultured podocytes and HN glomeruli) and COX-1 (HN glomeruli), production of prostanoids |
ROS | Superoxide production via NADPH oxidase and lipid peroxidation (HN) ROS production via xanthine oxidase pathway (HN) Generation of hydrogen peroxide by cytochrome P450 family of hemeprotein monooxygenases (cultured podocytes) |
Growth factors | Upregulation of platelet-derived growth factor B-chain, HB-EGF (HN), and Ret (HN and cultured mouse podocytes) Increase of p21 and p27 CDK inhibitors and decrease of CDK2 activity Decrease of p57 and increase of Cdc2, cyclins B1, B2, and D1 and phosphorylated histone-3 |
Transcription factors DNA damage | Activation of NF-κB (cultured podocytes and in vivo) Production of interleukin-8 and monocyte chemoattractant protein-1 Increase of p21, p53, GADD45, and checkpoint kinase-1 and kinase-2 (cultured podocytes and HN) |
Endocytosis Ectocytosis | Endocytosis (podocyte) Ectocytosis in membrane vesicles (urinary space) |
ER stress | Damage of ER membrane and unfolded protein response induction Upregulation of ER chaperones, PERK stimulation, eukaryotic translation initiation factor-2α subunit phosphorylation, and reduction of protein synthesis |
Ubiquitin–proteasome system | Polyubiquitination of glomerular proteins (HN) Upregulation of ubiquitin proteasome system (cultured podocytes) |
Podocyte cytoskeleton | Disassembly of F-actin filaments and focal adhesion complexes Increase of RhoA and decrease of Rac1 and Cdc42 activities (cultured podocytes) Foot process effacement by induction of active RhoA in podocytes (in mice) TRPC6 upregulation (cultured podocytes) |
Slit diaphragm | Decrease of nephrin mRNA and protein (HN) Dissociation of nephrin from actin cytoskeleton and loss of slit diaphragm integrity Alteration of podocin location and nephrin dissociation from podocin |
Cell cycle | Increased DNA synthesis without cell proliferation (podocyte) |
Anti-apoptosis | PI3K/Akt activation, Bad phosphorylation, and dissociation of the Bad/Bcl-XL complex Upregulation of caspase-8 inhibitor and cFLIPL and downregulation of FasL |
Pro-apoptosis | DNA damage via apoptosis regulating proteins (podocytes) |