Abstract
Roflumilast is a potent selective inhibitor of the phosphodiesterase-4 enzyme which greatly manifest an anti-inflammatory activity in chronic obstructive pulmonary patients. Inflammation is a prominent factor in the prevalence of diabetic nephropathy, one of the most prevalent microvascular complications of Diabetes Mellitus. The present study was undertaken to assess the potential role of roflumilast in diabetic nephropathy. 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 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, 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. In addition, 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 were observed in roflumilast treatment groups. Roflumilast treatment was shown to down-regulate the gene expressions of TNF-α (2.1-fold), NF-kB (2.3-fold), MCP-1 (2.5-fold), fibronectin (2.7-fold), collagen IV (2.7-fold), STAT 1(1.06-fold), and STAT 3 (1.20-fold) and upregulated the expression of the Nrf2 (1.43-fold) gene. Roflumilast manifested a potential role in diabetic nephropathy as a renoprotective agent. Roflumilast effectively down-regulates the JAK/STAT pathway and restores renal functions.
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Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- AGEs:
-
Advanced glycation End Products
- AMP:
-
Adenosine Monophosphate
- BUN:
-
Blood Urea Nitrogen
- BW:
-
Body Weight
- cAMP:
-
Cyclic Adenosine Monophosphate
- cDNA:
-
Complementary DNA
- CKD:
-
Chronic Kidney Disease
- CMC:
-
Carboxymethyl Cellulose
- COPD:
-
Chronic Obstructive Pulmonary Disease
- CTGF:
-
Connective Tissue Growth Factor
- DM:
-
Diabetes Mellitus
- DN:
-
Diabetic Nephropathy
- ECM:
-
Extracellular Matrix
- FBS:
-
Fasting Blood Sugar
- FINS:
-
Fasting Insulin
- GSH:
-
Reduced Glutathione
- GLUT 2:
-
Glucose transporter 2
- HbA1c:
-
Glycated Hemoglobin
- HFD:
-
High Fat Diet
- IL-6:
-
Interleukin 6
- IR:
-
Insulin Resistance
- JAK/STAT:
-
Janus kinase/signal transducers and activators of transcription
- KWI:
-
Kidney Weight Index
- MCP-1:
-
Monocyte Chemoattractant Protein-1
- MDA:
-
Malondialdehyde
- PDE:
-
Phosphodiesterase
- PKC:
-
Protein Kinase C
- ROS:
-
Reactive Oxygen Species
- SOD:
-
Superoxide Dismutase
- STZ:
-
Streptozotocin
- T2DM:
-
Type II Diabetes Mellitus
- TC:
-
Total Cholesterol
- TGF-β:
-
Transforming Growth Factor β
- TNF-α:
-
Tumor Necrosis Factor α
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Acknowledgements
The authors are thankful to Ramanbhai Patel College of Pharmacy, CHARUSAT, for providing the necessary infrastructure to carry out the research. We would also like to thank the knowledge consortium of Gujarat (KCG), India, for providing scholarship and contingency.
Funding
The authors are thankful to Ramanbhai Patel College of Pharmacy, CHARUSAT, for providing the necessary infrastructure to carry out the research. We would also like to thank the knowledge consortium of Gujarat (KCG), India, for providing scholarship and contingency. We are thankful to Ms. Pooja Gori for providing access to GraphPad Prism software.
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Sandip Patel, Manan Raval, and Priyal Patel conceptualized and designed the study. Material preparation, data collection, and analysis were performed by Priyal Patel and Shailesh Soni. Sandip Patel, Manan Raval, and Piyush Chudasama validated the data. The first draft of the manuscript was written by Priyal Patel, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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The animal study was approved by the Institutional Animal Ethics Committee at Ramanbhai Patel College of Pharmacy, CHARUSAT. (Registration number: 940/PO/Re/S/06/CPCSEA, Protocol Number: RPCP/IAEC/2021–2022/R01).
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Patel, P., Patel, S., Chudasama, P. et al. Roflumilast ameliorates diabetic nephropathy in rats through down-regulation of JAK/STAT signaling pathway. Naunyn-Schmiedeberg's Arch Pharmacol 396, 3285–3297 (2023). https://doi.org/10.1007/s00210-023-02535-0
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DOI: https://doi.org/10.1007/s00210-023-02535-0