Figure 1.

Molecular pathways involved in PKD, autophagy and apoptosis. Autophagy and apoptosis are intimately related. Pathways known to be activated in PKD are shown in red. The mTOR pathway that inhibits autophagy is activated in PKD [28]. There is cross talk between mTOR pathway of autophagy and the apoptosis pathways [129]. Bcl-2 is a central regulator of autophagy and apoptosis and functions by interacting with Beclin-1 and inhibiting autophagy. The pro-apoptotic mitochondrial protein, Bad, disrupts the interaction between Bcl-2 and Beclin-1 to induce autophagy. The pro-apoptotic protein, PUMA, a p53-inducible BH3-only protein, triggers mitochondrial-specific autophagy. Activation of caspase-3 and dysregulation of the balance between pro- and anti-apoptotic Bcl-2 family members, specifically a down-regulation of anti-apoptotic Bcl-xL, has been shown in PKD [9] and Bcl-2 downregulation worsens PKD [10]. Caspases activated during apoptosis can cleave and inactivate Beclin-1. Ambra-1, a key molecule that promotes the initial steps of autophagy, is irreversibly cleaved by both calpains and caspases. During apoptosis, Atg3 is cleaved by caspase 8 and cleaved Atg3 inhibits autophagy. Autophagy is inhibited by caspase-8-mediated cleavage of Beclin-1 [174]. The intrinsic and extrinsic pathways of caspase activation in apoptosis are activated in PKD [51]. In addition to the role that apoptosis-related proteins play in modulating autophagy, many autophagic proteins can induce apoptosis. mTOR forms a complex with PRAS40 and PRR5-like proteins to induce apoptosis. Activation of AMPK is known to inhibit mTOR and induce autophagy. AMPK activation with metformin is protective in PKD [152] but the effect of metformin on autophagy and apoptosis in PKD is not known. Atg12 increases mitochondrial apoptosis by directly binding to and inactivating Bcl-2. PKD mice have a significantly lower renal mRNA expression of Atg12 and other autophagy-related genes, Atg3, beclin1 and p62, [18].

Abbreviations: B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), p53 upregulated modulator of apoptosis (PUMA), proline-rich Akt substrate of 40 kDa (PRAS40), PRoline-Rich protein 5 (PRR5), activating molecule in Beclin1-regulated autophagy protein-1 (Ambra-1), 5’ AMP-activated protein kinase (AMPK).