Phosphodiesterase 4 inhibitors in diabetic nephropathy.

Phosphodiesterase subtype 4 (PDE4) hydrolyzes cyclic AMP, a secondary messenger that mediates intracellular signaling, and plays key roles in inflammatory and fibrotic responses. Based on these significant anti-inflammatory effects, oral administration of PDE4 inhibitor is approved for the treatment of chronic obstructive pulmonary disease, atopic dermatitis, and psoriasis. However, PDE4 inhibition also has adverse effects, such as diarrhea, vomiting, dyspepsia, and headache. Therefore, the application of PDE4 inhibitors for chronic diseases, such as diabetes and its complications, has not yet been approved. Recent studies have reported the clinical benefits of pentoxifylline, a non-selective PDE inhibitor, in patients with kidney disease. The PDE4 inhibitor, roflumilast, also clearly ameliorates the symptoms of diabetes mellitus by improving hyperglycemia and insulin resistance. However, the beneficial effects of PDE4 inhibition on diabetic nephropathy have not yet been evaluated, and its potential mechanisms of action remain unknown. In this review, we discuss the beneficial effects of PDE4 inhibitors and their mechanisms of action using diabetes and DN models.

Protective effect of a novel phosphodiesterase 4 selective inhibitor, compound A, in diabetic nephropathy model mice.

Phosphodiesterase subtype 4 (PDE4) hydrolyzes cyclic AMP (cAMP), a secondary messenger that mediates intracellular signaling, and plays key roles in inflammatory and profibrotic responses. Clinical benefits of pentoxifylline, a non-selective PDE inhibitor, have been reported in patients with kidney disease. Here, we identified compound A as a potent and selective PDE4 inhibitor and evaluated its potential as a novel therapeutic agent for diabetic nephropathy (DN). To determine its in vivo efficacy on DN, uninephrectomized (UNx-) db/db mice and KKAy mice were used as DN mice models. Eight-week repeated dosing with compound A (1-10 mg/kg, QD, p.o.) showed dose-dependent and significant suppressive effects on glycosylated hemoglobin (GHb) and urinary albumin/creatinine ratio (UACR) in UNx-db/db mice. These effects are more potent than irbesartan, a clinically approved angiotensin II receptor blocker of DN. Moreover, compound A suppressed pro-fibrotic and pro-inflammatory marker mRNAs and increased anti-reactive oxygen species marker mRNAs in the kidneys of UNx-db/db mice. The similar effect of compound A on UACR was also demonstrated by 8-week repeated dose in KKAy mice, another model for DN with intact leptin axis. Taken together, these data suggest that the PDE4-selective inhibitor compound A has potential as a new therapeutic agent for DN with multiple mechanisms of action including anti-diabetic, anti-fibrotic, and anti-reactive oxygen species effects.