Doxazosin down‐regulates sodium‐glucose cotransporter‐2 and exerts a renoprotective effect in rat models of acute renal injury

• Published in: Basic & clinical pharmacology & toxicology 2020-05, Vol.126 (5), p.413-423
• Main Authors: Rezq, Samar, Nasr, Ahmed M., Shaheen, Aya, Elshazly, Shimaa M.
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; acute renal injury; Animal models; Animals; Benzhydryl Compounds - pharmacology; Blood pressure; Blood Pressure - drug effects; Dinoprostone - metabolism; Down-Regulation - drug effects; Doxazosin - pharmacology; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Glucose; Glucosides - pharmacology; Glycerol; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia‐inducible factor 1; Immunology; Ischemia; Kidney - blood supply; Kidney - drug effects; Kidney - pathology; Kidneys; Kinases; Male; Malondialdehyde; Na+/glucose cotransporter; NAD(P)H oxidase; Nitric oxide; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Oxidative stress; Phosphorylation; Prostaglandin E2; Random Allocation; Rats; Reperfusion; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Rodents; Sodium; Sodium-Glucose Transporter 2 - metabolism; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; sodium‐glucose cotransporter 2
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/bcpt.13371

Sodium‐glucose cotransporter‐2 (SGLT2) is known to be involved in the progression of acute renal injury (ARI) and is regulated by different mediators in the kidneys including extracellular signal‐regulated kinase (ERK), hypoxia‐inducible factor 1 alpha (HIF1α) and prostaglandin E2 (PGE2). In the present study, we investigated the possible protective effect of doxazosin on renal ischaemia/reperfusion (IR) and glycerol‐induced ARI by determining its effect on SGLT2 via modifying ERK‐HIF1α pathway and/or PGE2. Rats were divided into control, sham or IR where the rats received the vehicle, doxazosin (8 mg/kg) or the SGLT2 inhibitor, dapagliflozin (10 mg/kg) for 3 days followed by 45 minutes bilateral renal ischaemia then 24 hours reperfusion. Another group of rats received the vehicle, doxazosin or dapagliflozin for three days followed by injection of 50% glycerol (8 mL/kg, IM) or saline. Kidney function tests, systolic blood pressure (SBP), oxidative stress markers (malondialdehyde [MDA] and NADPH oxidase), nitric oxide (NO), inducible nitric oxide synthase (iNOS), HIF1α, ERK phosphorylation and PGE2 levels were determined. Additionally, renal sections were used for immunological expression of SGLT2. ARI rats showed significantly increased SBP; worsened kidney function tests; increased oxidative stress, iNOS, NO, HIF1α levels; and decreased PGE2 and ERK phosphorylation along with up‐regulated SGLT2. Doxazosin treatment protected against the kidney damage and attenuated the associated biochemical changes. Doxazosin has a direct renoprotective effect possibly by down‐regulating SGLT2.