Improved Glycaemic Control and Nephroprotective Effects of Empagliflozin and Paricalcitol Co-Therapy in Mice with Type 2 Diabetes Mellitus.
Abdulrahman MujalliWesam F FarrashAhmad A ObaidAnmar A KhanRiyad Adnan AlmaimaniShakir IdrisMohamed Elzubier ElzubierElshiekh Babiker A KhidirAkhmed AslamFaisal MinshawiMohammad A AlobaidyAdel B AlharbiHussain A AlmasmoumMazen GhaithKhalid M AlquthamiBassem RefaatPublished in: International journal of molecular sciences (2023)
Herein, we measured the antidiabetic and nephroprotective effects of the sodium-glucose cotransporter-2 inhibitor (empagliflozin; SGLT2i) and synthetic active vitamin D (paricalcitol; Pcal) mono- and co-therapy against diabetic nephropathy (DN). Fifty mice were assigned into negative (NC) and positive (PC) control, SGLT2i, Pcal, and SGLT2i+Pcal groups. Following establishment of DN, SGLT2i (5.1 mg/kg/day) and/or Pcal (0.5 µg/kg/day) were used in the designated groups (5 times/week/day). DN was affirmed in the PC group by hyperglycaemia, dyslipidaemia, polyuria, proteinuria, elevated urine protein/creatinine ratio, and abnormal renal biochemical parameters. Renal SREBP-1 lipogenic molecule, adipokines (leptin/resistin), pro-oxidant (MDA/H 2 O 2 ), pro-inflammatory (IL1β/IL6/TNF-α), tissue damage (iNOS/TGF-β1/NGAL/KIM-1), and apoptosis (TUNEL/Caspase-3) markers also increased in the PC group. In contrast, renal lipolytic (PPARα/PPARγ), adiponectin, antioxidant (GSH/GPx1/SOD1/CAT), and anti-inflammatory (IL10) molecules decreased in the PC group. Both monotherapies increased insulin levels and mitigated hyperglycaemia, dyslipidaemia, renal and urine biochemical profiles alongside renal lipid regulatory molecules, inflammation, and oxidative stress. While SGLT2i monotherapy showed superior effects to Pcal, their combination demonstrated enhanced remedial actions related to metabolic control alongside renal oxidative stress, inflammation, and apoptosis. In conclusion, SGLT2i was better than Pcal monotherapy against DN, and their combination revealed better nephroprotection, plausibly by enhanced glycaemic control with boosted renal antioxidative and anti-inflammatory mechanisms.
Keyphrases
- oxidative stress
- anti inflammatory
- type diabetes
- dna damage
- cell death
- diabetic nephropathy
- diabetic rats
- metabolic syndrome
- ischemia reperfusion injury
- skeletal muscle
- endoplasmic reticulum stress
- magnetic resonance imaging
- fatty acid
- transforming growth factor
- clinical trial
- epithelial mesenchymal transition
- cell proliferation
- nitric oxide
- small molecule
- signaling pathway
- protein protein
- randomized controlled trial
- drug induced
- weight loss
- double blind
- study protocol