FIGURE 12.

A schematic shows pathways of interaction between NO and H₂S signaling pathways in podocytes incubated with tadalafil. Tadalafil stimulates NO generation by iNOS and activates soluble guanylyl cyclase to augment cGMP, which leads to an increase in CSE expression and H₂S generation; H₂S generation by CSE is required for tadalafil to promote phosphorylation of AMPK by calcium-calmodulin kinase kinase β (CaMKKβ), a Ca²⁺-dependent enzyme, and inhibit successively mTORC1 activity and events in mRNA translation, culminating in amelioration of high glucose-induced cellular hypertrophy and increase in matrix protein expression. Additionally, previous reports have shown that high glucose reduces AMP content in podocytes (7), which may also contribute to reduction in AMPK phosphorylation. BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester).