Role of calcium in polycystic kidney disease: From signaling to pathology

Figure 1 Diagram showing calcium-dependent dysregulated signaling pathways that promote cell proliferation and apoptosis in autosomal dominant polycystic kidney disease cells. Loss of PC1 and/or PC2 function causes a reduction in cytosolic calcium influx from three different cellular compartments: (1) the primary cilium after mechanical stimuli; (2) the endoplasmic reticulum, in an IP3R- and RyR-dependent manner; and (3) the plasma membrane, through a reduction in SOCE channel activity. The reduced concentration of cytosolic calcium may activate Ca²⁺ sensitive adenylyl cyclases 5 and 6, leading to a rise in cAMP. Increased levels of cAMP cause the activation of B-Raf/MEK/ERK and CREB/AREG/EGFR pathways, as well as stimulating mTOR signaling, through the active form of ERK kinases that inactivate the TSC1/TSC2 complex. Moreover, deficiency of PC1 and/or PC2 enhances the activity of NCCE channels, which, by increasing calcium oscillation frequency, results in the activation of the transcription factor NFAT. The abnormal activation of these signaling pathways promotes cell proliferation and kidney cyst formation. In addition, the reduction in Ca²⁺ influx from the ER to the cytosol caused by a deficiency in PC2 channel activity brings about an imbalance in ER calcium concentration, resulting in ER Ca²⁺ overload. The increased ER calcium concentration sensitizes kidney cystic cells to apoptotic stimuli by abnormal ER calcium release, which may induce mitochondrial damage and thereby lead to cytochrome C release and activation of apoptosis. AC 5/6: Adenylyl cyclase 5/6; AR: Amphiregulin; Ca²⁺ OX: Calcium oscillations; cAMP: Cyclic adenosine monophosphate; CREB: cAMP response element binding transcription factor; EGFR: Epidermal growth factor receptor; ER: Endoplasmic reticulum; ERK: Extracellular-signal-regulated kinases; GRB2: Growth factor receptor-bound protein 2; IP3R: Inositol 1,4,5-trisphosphate receptor; MEK: Mitogen-activated protein kinase kinase; mTOR: Mammalian target of rapamycin; NCCE: Non-capacitative calcium channel entry; NFAT: Nuclear factor of activated T-cells; PKA: Protein kinase A; PC1: Polycystin-1; PC2: Polycystin-2; S6K: Ribosomal S6 kinase; Raf: Rapidly accelerated fibrosarcoma kinase; Ras: Rat sarcoma viral oncogene homolog family; Rheb: Ras homolog enriched in brain; RyR: Ryanodine receptor; SERCA: Sarcoplasmic endoplasmic reticulum calcium ATPase; SOCE: Store-operated calcium channel entry; TRPC1: Transient receptor potential channel 1; TRPV4: Transient receptor potential cation channel subfamily V member 4; TSC: Tuberous sclerosis complex.