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Renal protective effect of nebivolol in rat models of acute renal injury: role of sodium glucose co-transporter 2

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Abstract

Background

Upregulation of the sodium glucose co-transporter (SGLT2) is implicated in acute renal injury (ARI) progression and is regulated by extracellular signal-regulated kinase (ERK), hypoxia-inducible factor 1 alpha (HIF1α) or prostaglandin E2 (PGE2). This study aimed to assess the possible protective effect of nebivolol on renal ischemia/reperfusion (IR) and glycerol-induced ARI targeting SGLT2 via modulating the ERK–HIF1α pathway.

Methods

Rats were divided into control, sham, IR or nebivolol-treated group, in which rats were treated with nebivolol (10 mg/kg) for 3 days prior to the induction of IR. The rats were subjected to renal ischemia by bilateral clamping of the pedicles for 45 min, followed by 24 h reperfusion. Another group of rats received the vehicle or nebivolol (10 mg/kg) for 3 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] and kidney levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS), HIF1α, ERK phosphorylation and PGE2 were determined. Additionally, renal sections were used for histological grading of renal injury and immunological expression of SGLT2.

Results

ARI rats showed significantly increased SBP, poor kidney function tests, increased oxidative stress, iNOS, NO, HIF1α levels, decreased PGE2 and ERK phosphorylation and upregulation of SGLT2 expression. Nebivolol treatment protected against the kidney damage both on the biochemical and histological levels.

Conclusion

Nebivolol has a direct renoprotective effect, at least in part, by down-regulating SGLT2 possibly via modulating HIF1α, ERK activity and PGE2 production.

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Abbreviations

ANOVA:

One-way analysis of variance

ARI:

Acute renal injury

ERK:

Extracellular signal-regulated kinase

eNOS:

Endothelial nitric oxide synthetase

GFR:

Glomerular filtration rate

GLY:

Glycerol

HE:

Hematoxylin and eosin

HIF1 α:

Hypoxia-inducible factor 1 alpha

IHC:

Immunohistochemistry

iNOS:

Inducible nitric oxide synthetase

IR:

Ischemia/reperfusion

MDA:

Malondialdehyde

NADPH oxidase:

Nicotinamide adenine dinucleotide phosphate oxidase

NO:

Nitric oxide

PGE2:

Prostaglandin E2

ROS:

Reactive oxygen species

SBP:

Systolic blood pressure

SEM:

Standard error of the mean

SGLT2:

Sodium glucose co-transporter 2

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This work did not receive any funding from funding agencies in the public, commercial, or not-for-profit sectors.

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Author notes

  1. Ahmed M. Nasr and Samar Rezq have contributed equally to the work.

Authors and Affiliations

  1. Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, Egypt

    Ahmed M. Nasr & Aya Shaheen

  2. Pharmacology and Toxicology Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt

    Samar Rezq & Shimaa M. Elshazly

  3. Department of Cell and Molecular Biology, UMMC, 2500 N State St., Jackson, MS, 39216, USA

    Samar Rezq

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  1. Ahmed M. Nasr
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Correspondence to Samar Rezq.

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Nasr, A.M., Rezq, S., Shaheen, A. et al. Renal protective effect of nebivolol in rat models of acute renal injury: role of sodium glucose co-transporter 2. Pharmacol. Rep 72, 956–968 (2020). https://doi.org/10.1007/s43440-020-00059-5

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