Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 894, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2021.173852
Keywords
Phosphodiesterase 4 inhibitor; Compound a; Diabetic nephropathy; Uninephrectomy; UACR; Db/db mouse
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The study identified compound A as a potent and selective PDE4 inhibitor with therapeutic potential for diabetic nephropathy. The compound showed significant effects on glycosylated hemoglobin and urinary albumin/creatinine ratio in DN mouse models, suggesting it may offer a new treatment option with anti-diabetic, anti-fibrotic, and anti-reactive oxygen species effects.
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 KKA(y) 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 proinflammatory 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 KKA(y) 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.
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