Diabetes nephropathy (DN) is one of the most prevalent microvascular
complications of Diabetes Mellitus (DM). The present study was carried
out to explore the role of roflumilast, a PDE4 inhibitor, as a potential
treatment option for DN. The model was developed by feeding a high-fat
diet for four weeks and following streptozotocin (30 mg/kg) injection
intraperitoneally. The rats with >13.8 mmol/L blood glucose
were included in the study. The diabetic rats were treated with
roflumilast (0.25, 0.5, 1 mg/kg) and standard metformin (100 mg/kg)
orally once a day for eight weeks. Roflumilast (1 mg/kg) remarkably
improved renal damage, which was indicated by an increase in 16%
albumin, a decrease in 5% serum creatinine, 12% BUN, 19% HbA1c, and
34% blood glucose. It also significantly improves the oxidative stress
levels, which was indicated by a decrease in 18% MDA level and an
increase in GSH, SOD, and catalase by 6%, 4%, and 5%, respectively.
Roflumilast (1 mg/kg) decreased the HOMA-IR index by 28% and increased
the pancreatic β-cells functioning by 30%. Moreover, significant
improvement in histopathological abnormalities was observed in
roflumilast treatment groups. Roflumilast treatment was shown to
down-regulate the gene expression of TNF-α, NF-kB, MCP-1, fibronectin,
and collagen IV, and upregulated the expression of the Nrf2 gene. The
gene expression was significantly reduced by 2.1-fold, 2.3-fold,
2.5-fold, 2.7-fold, and 1.52-fold individually. The Nrf2 gene was
upregulated by 1.43-fold. These results manifested that roflumilast
alleviated renal injuries in DN rats, which might be associated with
suppressing the JAK/STAT signaling pathway.
