Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney

Autor: Federica Genovese, Dora Balogh, Sandor Koszegi, Attila J. Szabo, Lilla Lenart, Adam Hosszu, Judit Hodrea, Nadja Sparding, Andrea Fekete, László Wagner, Balázs Besztercei
Rok vydání: 2020
Předmět:
Blood Glucose
Male
Na+-glucose cotransporter 2 inhibitors
0301 basic medicine
Glycosylation
Physiology
kidney fibrosis
030204 cardiovascular system & hematology
Pharmacology
Streptozocin
Cell Line
Diabetes Mellitus
Experimental
Kidney Tubules
Proximal
03 medical and health sciences
chemistry.chemical_compound
O-GlcNAcylation
0302 clinical medicine
Glucosides
Fibrosis
Diabetes mellitus
Renal fibrosis
medicine
Animals
Humans
Diabetic Nephropathies
Benzhydryl Compounds
Rats
Wistar
Dapagliflozin
Sodium-Glucose Transporter 2 Inhibitors
tubular hypoxia
Kidney
diabetes
business.industry
Hypoxia (medical)
medicine.disease
Streptozotocin
Cell Hypoxia
Fibronectins
Diabetes Mellitus
Type 1
030104 developmental biology
medicine.anatomical_structure
chemistry
Collagen
SGLT2 Inhibitor
medicine.symptom
business
Research Article
medicine.drug
Zdroj: Hodrea, J, Balogh, D B, Hosszu, A, Lenart, L, Besztercei, B, Koszegi, S, Sparding, N, Genovese, F, Wagner, L J, Szabo, A J & Fekete, A 2020, ' Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney ', American journal of physiology. Renal physiology, vol. 318, no. 4, pp. F1017-F1029 . https://doi.org/10.1152/ajprenal.00021.2020
American Journal of Physiology-Renal Physiology
ISSN: 1522-1466
1931-857X
DOI: 10.1152/ajprenal.00021.2020
Popis: Diabetic kidney disease is a worldwide epidemic, and therapies are incomplete. Clinical data suggest that improved renal outcomes by Na+-glucose cotransporter 2 inhibitor (SGLT2i) are partly beyond their antihyperglycemic effects; however, the mechanisms are still elusive. Here, we investigated the effect of the SGLT2i dapagliflozin (DAPA) in the prevention of elevated O-GlcNAcylation and tubular hypoxia as contributors of renal fibrosis. Type 1 diabetes was induced by streptozotocin in adult male Wistar rats. After the onset of diabetes, rats were treated for 6 wk with DAPA or DAPA combined with losartan (LOS). The effect of hyperglycemia was tested in HK-2 cells kept under normal or high glucose conditions. To test the effect of hypoxia, cells were kept in 1% O2 for 2 h. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed the loss of renal function, mitigated renal tubular injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and reduced tubulointerstitial fibrosis. DAPA diminished high glucose-induced protein O-GlcNAcylation and moderated the tubular response to hypoxia through the hypoxia-inducible factor pathway. DAPA alone was as effective as combined treatment with LOS in all outcome parameters. These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia, and fibrosis, a vicious trio that could be targeted by SGLT2i in kidney diseases of other origins as well.
Databáze: OpenAIRE
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