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O-Linked GlcNAcylation mediates the inhibition of proximal tubule (Na++K+)ATPase activity in the early stage of diabetes mellitus

Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus (DM). It has been proposed that modifications in the function of proximal tubule epithelial cells (PTECs) precede glomerular damage during the onset of DKD. This study aimed to identify modifications in renal sodium handling...

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Published in:Biochimica et biophysica acta. General subjects 2023-11, Vol.1867 (11), p.130466-130466, Article 130466
Main Authors: Silva-Aguiar, Rodrigo P., Teixeira, Douglas E., Peres, Rodrigo A.S., Alves, Sarah A.S., Novaes-Fernandes, Carolina, Dias, Wagner B., Pinheiro, Ana Acacia S., Peruchetti, Diogo B., Caruso-Neves, Celso
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container_end_page 130466
container_issue 11
container_start_page 130466
container_title Biochimica et biophysica acta. General subjects
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creator Silva-Aguiar, Rodrigo P.
Teixeira, Douglas E.
Peres, Rodrigo A.S.
Alves, Sarah A.S.
Novaes-Fernandes, Carolina
Dias, Wagner B.
Pinheiro, Ana Acacia S.
Peruchetti, Diogo B.
Caruso-Neves, Celso
description Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus (DM). It has been proposed that modifications in the function of proximal tubule epithelial cells (PTECs) precede glomerular damage during the onset of DKD. This study aimed to identify modifications in renal sodium handling in the early stage of DM and its molecular mechanism. Streptozotocin (STZ)-induced diabetic BALB/c mice (STZ group) and LLC-PK1 cells, a model of PTECs, were used. All parameters were assessed in the 4th week after an initial injection of STZ. Early stage of DKD was characterized by hyperfiltration and PTEC dysfunction. STZ group exhibited increased urinary sodium excretion due to impairment of tubular sodium reabsorption. This was correlated to a decrease in cortical (Na++K+)ATPase (NKA) α1 subunit expression and enzyme activity and an increase in O-GlcNAcylation. RNAseq analysis of patients with DKD revealed an increase in expression of the glutamine-fructose aminotransferase (GFAT) gene, a rate-limiting step of hexosamine biosynthetic pathway, and a decrease in NKA expression. Incubation of LLC-PK1 cells with 10 μM thiamet G, an inhibitor of O-GlcNAcase, reduced the expression and activity of NKA and increased O-GlcNAcylation. Furthermore, 6-diazo-5-oxo-L-norleucine (DON), a GFAT inhibitor, or dapagliflozin, an SGLT2 inhibitor, avoided the inhibitory effect of HG on expression and activity of NKA associated with the decrease in O-GlcNAcylation. Our results show that the impairment of tubular sodium reabsorption, in the early stage of DM, is due to SGLT2-mediated HG influx in PTECs, increase in O-GlcNAcylation and reduction in NKA expression and activity. •Renal (Na++K+)ATPase, NKA, is inhibited in early diabetes.•Proximal tubule injury correlates with inhibition of NKA.•O-GlcNAcylation inhibits NKA activity in proximal tubule cells.•Glucose flux through the hexosamine biosynthetic pathway inhibits NKA activity.
doi_str_mv 10.1016/j.bbagen.2023.130466
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It has been proposed that modifications in the function of proximal tubule epithelial cells (PTECs) precede glomerular damage during the onset of DKD. This study aimed to identify modifications in renal sodium handling in the early stage of DM and its molecular mechanism. Streptozotocin (STZ)-induced diabetic BALB/c mice (STZ group) and LLC-PK1 cells, a model of PTECs, were used. All parameters were assessed in the 4th week after an initial injection of STZ. Early stage of DKD was characterized by hyperfiltration and PTEC dysfunction. STZ group exhibited increased urinary sodium excretion due to impairment of tubular sodium reabsorption. This was correlated to a decrease in cortical (Na++K+)ATPase (NKA) α1 subunit expression and enzyme activity and an increase in O-GlcNAcylation. RNAseq analysis of patients with DKD revealed an increase in expression of the glutamine-fructose aminotransferase (GFAT) gene, a rate-limiting step of hexosamine biosynthetic pathway, and a decrease in NKA expression. Incubation of LLC-PK1 cells with 10 μM thiamet G, an inhibitor of O-GlcNAcase, reduced the expression and activity of NKA and increased O-GlcNAcylation. Furthermore, 6-diazo-5-oxo-L-norleucine (DON), a GFAT inhibitor, or dapagliflozin, an SGLT2 inhibitor, avoided the inhibitory effect of HG on expression and activity of NKA associated with the decrease in O-GlcNAcylation. 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RNAseq analysis of patients with DKD revealed an increase in expression of the glutamine-fructose aminotransferase (GFAT) gene, a rate-limiting step of hexosamine biosynthetic pathway, and a decrease in NKA expression. Incubation of LLC-PK1 cells with 10 μM thiamet G, an inhibitor of O-GlcNAcase, reduced the expression and activity of NKA and increased O-GlcNAcylation. Furthermore, 6-diazo-5-oxo-L-norleucine (DON), a GFAT inhibitor, or dapagliflozin, an SGLT2 inhibitor, avoided the inhibitory effect of HG on expression and activity of NKA associated with the decrease in O-GlcNAcylation. 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It has been proposed that modifications in the function of proximal tubule epithelial cells (PTECs) precede glomerular damage during the onset of DKD. This study aimed to identify modifications in renal sodium handling in the early stage of DM and its molecular mechanism. Streptozotocin (STZ)-induced diabetic BALB/c mice (STZ group) and LLC-PK1 cells, a model of PTECs, were used. All parameters were assessed in the 4th week after an initial injection of STZ. Early stage of DKD was characterized by hyperfiltration and PTEC dysfunction. STZ group exhibited increased urinary sodium excretion due to impairment of tubular sodium reabsorption. This was correlated to a decrease in cortical (Na++K+)ATPase (NKA) α1 subunit expression and enzyme activity and an increase in O-GlcNAcylation. RNAseq analysis of patients with DKD revealed an increase in expression of the glutamine-fructose aminotransferase (GFAT) gene, a rate-limiting step of hexosamine biosynthetic pathway, and a decrease in NKA expression. Incubation of LLC-PK1 cells with 10 μM thiamet G, an inhibitor of O-GlcNAcase, reduced the expression and activity of NKA and increased O-GlcNAcylation. Furthermore, 6-diazo-5-oxo-L-norleucine (DON), a GFAT inhibitor, or dapagliflozin, an SGLT2 inhibitor, avoided the inhibitory effect of HG on expression and activity of NKA associated with the decrease in O-GlcNAcylation. Our results show that the impairment of tubular sodium reabsorption, in the early stage of DM, is due to SGLT2-mediated HG influx in PTECs, increase in O-GlcNAcylation and reduction in NKA expression and activity. •Renal (Na++K+)ATPase, NKA, is inhibited in early diabetes.•Proximal tubule injury correlates with inhibition of NKA.•O-GlcNAcylation inhibits NKA activity in proximal tubule cells.•Glucose flux through the hexosamine biosynthetic pathway inhibits NKA activity.</abstract><pub>Elsevier B.V</pub><doi>10.1016/j.bbagen.2023.130466</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record>
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ispartof Biochimica et biophysica acta. General subjects, 2023-11, Vol.1867 (11), p.130466-130466, Article 130466
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source ScienceDirect Journals
subjects adenosinetriphosphatase
biochemical pathways
Diabetes
diabetes mellitus
Diabetic kidney disease
enzyme activity
epithelium
excretion
genes
GlcNAc
hexosamines
Kidney
kidney diseases
Natriuresis
O-linked GlcNAcylation
Proximal tubule
reaction kinetics
resorption
sodium
sodium glucose cotransporter-2 inhibitors
Sodium pump
Sodium transport
streptozotocin
Urinary sodium excretion
title O-Linked GlcNAcylation mediates the inhibition of proximal tubule (Na++K+)ATPase activity in the early stage of diabetes mellitus
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