Amelioration of Diabetic Nephropathy by Targeting Autophagy via Rapamycin or Fasting: Relation to Cell Apoptosis/Survival

Abstract

Autophagy has been demonstrated to have a beneficial effect on diabetic nephropathy (DN). Rapamycin, an inhibitor of mTOR, was shown to stimulate β-cell autophagy. However, its effects on preventing or ameliorating DN is unclear, and its effects are worth studying. As fasting is now an attractive protective strategy, we aim to compare its effect to rapamycin effects on pancreatic and renal cells. Twenty-eight adult male Wistar Albino rats were randomly divided into four groups, using streptozotocin (STZ) to induce diabetes mellitus (DM). Autophagy was induced by two ways; rapamycin or fasting. The extent of autophagy and apoptosis were investigated by measuring the level of LC3B and p53 proteins, respectively, in pancreatic and kidney tissues using Western blotting (WB) technique and imaging the renal cells under transmission electron microscope. The efflux transporter P-glycoprotein was quantified by WB as well. Rapamycin-induced autophagy occurred concurrently with apoptosis. On the other hand, fasting supported P-glycoprotein recovery and renal cell survival together with disabling β-cells apoptosis. In conclusion, this study provides a potential link between rapamycin or fasting for the cross-regulation of apoptosis and autophagy in the setting of cell stress as DN. Unlike rapamycin, fasting enhanced the active expression of ABCB1 efflux protein, providing insights on the potential ameliorative effects of fasting in DN that require further elucidation.

Programmed Cell Death in Diabetic Nephropathy: A Review of Apoptosis, Autophagy, and Necroptosis

“…Thus, a calorie restriction regimen must be regarded as an effective therapeutic approach to inhibit diabetic nephropathy. Calorie restriction enhances renal impairment in type II diabetic Wistar fatty rats, and it repairs autophagy activity in their proximal tubular cells [ 147 ]. Therefore, an agent that can imitate caloric restriction might be a potential therapy for diabetic nephropathy by inducing autophagy in mammalian cells.…”

“…Thus, rapamycin might be protective in diabetic nephropathy by activating autophagy. However, extreme mTORC1 prevention impairs podocyte function, suggesting that further investigation is required regarding the safety and effectiveness of mTORC1 prevention in patients with diabetic nephropathy [ 147 , 148 ].…”

Intermittent Fasting—A Healthy Dietary Pattern for Diabetic Nephropathy

“…Moreover, IF also improved the peripheral and central changes induced by a high-fat diet by maintaining the balance of autophagy [ 90 ]. The direct evidence linking IF, autophagy, and DN was demonstrated by Gouda et al in an STZ-induced DN mice model, where apoptosis was increased, and autophagy was inhibited, while fasting restored renal autophagy, reduced apoptosis, and alleviated kidney injury [ 91 ] ( Figure 2 ). Although the molecular mechanism underlying autophagy activation by IF in DN remains to be studied further, it is confirmed that IF-mediated autophagy activation is an effective protective strategy against DN.…”