P2X7 siRNA targeted to the kidneys increases klotho and delays the progression of experimental diabetic nephropathy
A M Rodrigues1,2, R S Serralha1,2, D Y Lima2,3
1Translational Medicine, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
Abstract:
Previous studies in our laboratory have suggested that P2X7 could contribute to the progression of diabetic nephropathy and modulated klotho expression. The aim of this study was to investigate if P2X7 receptor is related to the expression of klotho in the onset of diabetic nephropathy in rats. Seven-week-old male Wistar rats weighing 210 g were all uninephrectomized; two-third of the animals were induced to diabetes with 60 mg/kg streptozotocin i.v., and one-third received its vehicle (control rats). At 4th day of the fifth week of the protocol, half of the diabetic rats received a small interfering RNA targeting for P2X7 mRNA, and the other half received its vehicle. Euthanasia was made at the eighth week. Diabetic animals reproduced all classic symptoms of the disease; besides, they showed reduced renal function and low NO bioavailability; also, SOD1, SOD2, and catalase were increased, probably due to the oxidative stress which was elevated in this situation. Metabolic data of diabetic rats did not change by silencing P2X7 receptor. For the other hand, silencing P2X7 was able to contribute to balance oxidative and nitrosative profile, ultimately improving the renal function and increasing plasma and membrane forms of klotho. These findings suggest that the management of P2X7 receptor can benefit the kidneys with diabetic nephropathy. Further studies are needed to show the therapeutic potential of this receptor inhibition to provide a better quality of life for the diabetic patient.
Insights
Targeting the P2X7 receptor may improve kidney function in diabetic nephropathy by balancing oxidative stress and increasing klotho. This suggests P2X7 receptor inhibition as a potential therapeutic strategy.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Diabetic nephropathy is a major complication of diabetes, characterized by kidney damage.
- Previous research suggests a role for the P2X7 receptor in diabetic nephropathy progression and its modulation of klotho expression.
- The precise relationship between P2X7 receptor and klotho in the early stages of diabetic nephropathy requires further investigation.
Purpose of the Study:
- To investigate the relationship between the P2X7 receptor and klotho expression in the onset of diabetic nephropathy in a rat model.
- To determine if P2X7 receptor inhibition affects renal function, oxidative stress, and klotho levels in diabetic rats.
Main Methods:
- Male Wistar rats were induced into diabetes using streptozotocin and treated with a P2X7 receptor-targeting small interfering RNA or vehicle.
- Renal function, oxidative stress markers (SOD1, SOD2, catalase), nitric oxide (NO) bioavailability, and klotho levels were assessed.
- Metabolic parameters were monitored throughout the study.
Main Results:
- Diabetic rats exhibited reduced renal function, low NO bioavailability, and increased oxidative stress markers.
- Silencing the P2X7 receptor did not alter metabolic data but improved renal function and balanced oxidative and nitrosative stress.
- P2X7 receptor inhibition led to increased plasma and membrane forms of klotho.
Conclusions:
- The P2X7 receptor plays a role in the development of diabetic nephropathy, influencing oxidative stress and klotho expression.
- Inhibition of the P2X7 receptor shows therapeutic potential for managing diabetic nephropathy by improving renal function and increasing klotho.
- Targeting the P2X7 receptor could offer a novel strategy to enhance the quality of life for patients with diabetic nephropathy.
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