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.