Anti-Inflammatory and Anti-apoptotic Effects of Phosphodiesterase Inhibitors Against Streptozocin-induced Diabetic Nephropathy

BACKGROUND/AIM: A variety of actions implicated in diabetic nephropathy (DN) are attributed to inflammatory cytokines and apoptosis of tubular epithelial cells. Building on our previous research demonstrating the role of different phosphodiesterase inhibitors (PDEIs) in improving renal microcirculation, glucose lowering, and antioxidant effects in rats with DN, this study aims to further explore the anti-inflammatory and anti-apoptotic properties of PDEIs by measuring their effects on renal expression of pro-inflammatory cytokines in streptozocin (STZ)-induced diabetic nephropathic rats. MATERIALS AND METHODS: Out of 50 adult male Sprague-Dawley rats, diabetes was induced in 40 rats by a single injection of STZ (45 mg/kg) dissolved in citrate buffer. Ten days after induction of diabetes, rats were divided into five groups (10/group): normal control, diabetic control, and 3 diabetic groups treated with pentoxifylline, sildenafil, and milrinone via drinking water for 15 successive days. Serum and kidney tissue samples were collected to evaluate the effect of treatment with PDEIs on diabetes-induced histopathological changes and expression levels of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), apoptotic marker Bcl-2 Associated X-protein (Bax) and anti-apoptotic marker B cell lymphoma-2 (Bcl-2) in rat's kidneys. RESULTS: A significant increase in pro-inflammatory cytokines (TNF-α and IL-6), and apoptosis marker (Bax), with a concomitant decrease in anti-apoptotic protein (Bcl-2) were observed in diabetic rats. Treatment with PDEIs resulted in a significant decrease in renal expression of Bax, TNF-α, and IL-6, with an increase Bcl-2 expression, with slight, though not statistically significant, differences among the PDEI-treated groups. CONCLUSION: The tested PDEIs, pentoxifylline, sildenafil, and milrinone, exhibit significant anti-inflammatory and anti-apoptotic effects, highlighting their potential in slowing the progression of diabetic nephropathy.