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

Abstract

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. K E Y W O R D Sacute renal injury, extracellular signal-regulated kinase, hypoxia-inducible factor 1, prostaglandin E2, sodium-glucose cotransporter 2 414 | REZQ Et al.

Glucose Metabolism in Acute Kidney Injury and Kidney Repair

“…In addition, using renal tubular epithelial cell-specific PKM2-knockout mice (Pkm2 − / − ) mice, Zhou et al proved that Pkm2 − / − mice had better renal function and less histological tubular injury than wild-type (WT) mice following renal IRI or lipopolysaccharide (LPS)-induced endotoxic AKI (66). Several studies reported the protective effect of SGLT2 inhibitors in IRI-induced AKI (67)(68)(69), but a recent study showed that genetic deletion of SGLT2 from renal tubules did not protect against renal IRI (70). Therefore, the role of SGLTs in ischemic AKI remains to be established.…”

SGLT2 inhibition promotes glomerular repopulation by cells of renin lineage in experimental kidney disease

“…Despite the increased CoRL‐derived cells observed in glomeruli, renal function did not change upon SGLT2 inhibition in bIRI exposed animals in our study setup. There have been several rodent studies reporting improved renal function and morphology after ischaemic injury comparing SGLT2 inhibitory treatment with placebo 40–43 . However, the majority of these start treatment well ahead of injury induction and terminate the experiment already after 24–48 h of reperfusion time.…”

Prazosin Treatment Protects Brain and Heart by Diminishing Oxidative Stress and Apoptotic Pathways After Renal Ischemia Reperfusion

“…For instance, doxazocin has been shown to protect against renal IR injury via decreasing oxidative stress, nitric oxide, and inducible nitric oxide synthase. Also, doxazosin treatment could significantly attenuate hypoxia-inducible factor 1 alpha and downregulate sodium-glucose cotransporter-2 [42]. It is reported, prazosin, a selective α1-adrenoceptor antagonist, could effectively decrease creatinine and urea as a marker of renal dysfunction.…”