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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 |
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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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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.</description><identifier>ISSN: 0304-4165</identifier><identifier>EISSN: 1872-8006</identifier><identifier>DOI: 10.1016/j.bbagen.2023.130466</identifier><language>eng</language><publisher>Elsevier B.V</publisher><subject>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</subject><ispartof>Biochimica et biophysica acta. General subjects, 2023-11, Vol.1867 (11), p.130466-130466, Article 130466</ispartof><rights>2023 Elsevier B.V.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c321t-8b1e4a428986458a7c17212091d1148b58c14afef3d5a05743ecab0e0fe82e63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids></links><search><creatorcontrib>Silva-Aguiar, Rodrigo P.</creatorcontrib><creatorcontrib>Teixeira, Douglas E.</creatorcontrib><creatorcontrib>Peres, Rodrigo A.S.</creatorcontrib><creatorcontrib>Alves, Sarah A.S.</creatorcontrib><creatorcontrib>Novaes-Fernandes, Carolina</creatorcontrib><creatorcontrib>Dias, Wagner B.</creatorcontrib><creatorcontrib>Pinheiro, Ana Acacia S.</creatorcontrib><creatorcontrib>Peruchetti, Diogo B.</creatorcontrib><creatorcontrib>Caruso-Neves, Celso</creatorcontrib><title>O-Linked GlcNAcylation mediates the inhibition of proximal tubule (Na++K+)ATPase activity in the early stage of diabetes mellitus</title><title>Biochimica et biophysica acta. General subjects</title><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.</description><subject>adenosinetriphosphatase</subject><subject>biochemical pathways</subject><subject>Diabetes</subject><subject>diabetes mellitus</subject><subject>Diabetic kidney disease</subject><subject>enzyme activity</subject><subject>epithelium</subject><subject>excretion</subject><subject>genes</subject><subject>GlcNAc</subject><subject>hexosamines</subject><subject>Kidney</subject><subject>kidney diseases</subject><subject>Natriuresis</subject><subject>O-linked GlcNAcylation</subject><subject>Proximal tubule</subject><subject>reaction kinetics</subject><subject>resorption</subject><subject>sodium</subject><subject>sodium glucose cotransporter-2 inhibitors</subject><subject>Sodium pump</subject><subject>Sodium transport</subject><subject>streptozotocin</subject><subject>Urinary sodium excretion</subject><issn>0304-4165</issn><issn>1872-8006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNqFkc1O6zAQhS10kegF3oCFl6AqxWM7jru5UoX4ExWw6N5ynAm4N00gdhBd8ua4hDV4Y2l0vqMzcwg5ATYDBup8PStL-4TtjDMuZiCYVGqPTEAXPNOMqT9kwtIwk6DyA_I3hDVLL5_nE_LxkC19-x8ret24-4XbNjb6rqUbrLyNGGh8RurbZ1_6r3lX05e-e_cb29A4lEOD9PTeTqd307PF6tEGpNZF_-bjNlFfMNq-2dIQU8AdnWxL3BlvsGl8HMIR2a9tE_D4-z8kq6vL1cVNtny4vr1YLDMnOMRMl4DSSq7nWslc28JBwYGzOVQAUpe5diBtjbWocsvyQgp0tmTIatQclTgkp6Ntiv86YIhm44NLGWyL3RCMgFyAnkv-u5RrpVXBmJBJKkep67sQeqzNS59u028NMLPrxqzN2I3ZdWPGbhL2b8QwLfzmsTfBeWxdOnqPLpqq8z8bfAJr9pjd</recordid><startdate>202311</startdate><enddate>202311</enddate><creator>Silva-Aguiar, Rodrigo P.</creator><creator>Teixeira, Douglas E.</creator><creator>Peres, Rodrigo A.S.</creator><creator>Alves, Sarah A.S.</creator><creator>Novaes-Fernandes, Carolina</creator><creator>Dias, Wagner B.</creator><creator>Pinheiro, Ana Acacia S.</creator><creator>Peruchetti, Diogo B.</creator><creator>Caruso-Neves, Celso</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope></search><sort><creationdate>202311</creationdate><title>O-Linked GlcNAcylation mediates the inhibition of proximal tubule (Na++K+)ATPase activity in the early stage of diabetes mellitus</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c321t-8b1e4a428986458a7c17212091d1148b58c14afef3d5a05743ecab0e0fe82e63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>adenosinetriphosphatase</topic><topic>biochemical pathways</topic><topic>Diabetes</topic><topic>diabetes mellitus</topic><topic>Diabetic kidney disease</topic><topic>enzyme activity</topic><topic>epithelium</topic><topic>excretion</topic><topic>genes</topic><topic>GlcNAc</topic><topic>hexosamines</topic><topic>Kidney</topic><topic>kidney diseases</topic><topic>Natriuresis</topic><topic>O-linked GlcNAcylation</topic><topic>Proximal tubule</topic><topic>reaction kinetics</topic><topic>resorption</topic><topic>sodium</topic><topic>sodium glucose cotransporter-2 inhibitors</topic><topic>Sodium pump</topic><topic>Sodium transport</topic><topic>streptozotocin</topic><topic>Urinary sodium excretion</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Silva-Aguiar, Rodrigo P.</creatorcontrib><creatorcontrib>Teixeira, Douglas E.</creatorcontrib><creatorcontrib>Peres, Rodrigo A.S.</creatorcontrib><creatorcontrib>Alves, Sarah A.S.</creatorcontrib><creatorcontrib>Novaes-Fernandes, Carolina</creatorcontrib><creatorcontrib>Dias, Wagner B.</creatorcontrib><creatorcontrib>Pinheiro, Ana Acacia S.</creatorcontrib><creatorcontrib>Peruchetti, Diogo B.</creatorcontrib><creatorcontrib>Caruso-Neves, Celso</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Biochimica et biophysica acta. General subjects</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Silva-Aguiar, Rodrigo P.</au><au>Teixeira, Douglas E.</au><au>Peres, Rodrigo A.S.</au><au>Alves, Sarah A.S.</au><au>Novaes-Fernandes, Carolina</au><au>Dias, Wagner B.</au><au>Pinheiro, Ana Acacia S.</au><au>Peruchetti, Diogo B.</au><au>Caruso-Neves, Celso</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>O-Linked GlcNAcylation mediates the inhibition of proximal tubule (Na++K+)ATPase activity in the early stage of diabetes mellitus</atitle><jtitle>Biochimica et biophysica acta. General subjects</jtitle><date>2023-11</date><risdate>2023</risdate><volume>1867</volume><issue>11</issue><spage>130466</spage><epage>130466</epage><pages>130466-130466</pages><artnum>130466</artnum><issn>0304-4165</issn><eissn>1872-8006</eissn><abstract>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.</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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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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