NCS 613, a PDE4 inhibitor, by increasing cAMP level suppresses systemic inflammation and immune complexes deposition in kidney of MRL/lpr lupus- prone mice.

Nephritis remains the most common severe manifestation of systemic lupus erythematosus in which auto-antibodies mediate chronic inflammation and kidney damage. cAMP-phosphodiesterases regulate sodium excretion and inflammation in various tissues. How cAMP elevation can reduce systemic inflammation and suppress kidney inflammation and damage remains elusive. PDE4 signaling and cAMP metabolism were investigated along immune complex depositions in target tissues and kidney damage (histology). SLE disease progression is associated with changes in kidney PDE4 activity and expression. Moreover, lupus prone mice exhibit low kidney cAMP level which is associated to induction and relocation of nuclear and cytoskeleton PDE4 isoforms. Auto-antibodies-induced kidney damage was attested by mesangial proliferation and cellular infiltration. Interestingly, we reported that NCS 613 treatment decreases systemic auto-antibody secretion and their corresponding immune complex deposition in target tissues. Furthermore, NCS 613 is able to increase cAMP levels in the kidney; hence this compound rescues kidney PDE4 alterations in treated mice. NCS 613 overcomes disease progression in lupus prone mice by improving wellbeing and decreasing inflammation in treated mice. The PDE4 inhibitor, NCS 613, is a new anti-inflammatory compound that is believed to be a leading drug candidate for the treatment of inflammatory diseases such as lupus nephritis.