Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Carrier Proteins
/ metabolism
Cells, Cultured
Diabetes Mellitus, Experimental
/ metabolism
Glucosides
/ pharmacology
Humans
Hypertension
/ etiology
Kidney Tubules, Distal
/ cytology
Mice
Mice, Obese
Microfilament Proteins
/ genetics
Phosphorylation
Protein Kinase C
/ metabolism
Sensitivity and Specificity
Signal Transduction
Sodium-Glucose Transporter 2 Inhibitors
/ pharmacology
Solute Carrier Family 12, Member 3
/ metabolism
Thiophenes
/ pharmacology
WNK Lysine-Deficient Protein Kinase 1
/ metabolism
Cell Signaling
Na transport
diabetes mellitus
distal tubule
hyperglycemia
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
10
07
2018
accepted:
08
02
2019
pubmed:
28
3
2019
medline:
28
2
2020
entrez:
28
3
2019
Statut:
ppublish
Résumé
Mechanisms underlying the frequent association between salt-sensitive hypertension and type 2 diabetes remain obscure. We previously found that protein kinase C (PKC) activation phosphorylates Kelch-like 3 (KLHL3), an E3 ubiquitin ligase component, at serine 433. We investigated whether impaired KLHL3 activity results in increased renal salt reabsorption We used the db/db diabetes mouse model to explore KLHL3's role in renal salt handling in type 2 diabetes and evaluated mechanisms of KLHL3 dysregulation in cultured cells. We observed PKC activity in the db/db mouse kidney and phosphorylation of serine 433 in KLHL3 (KLHL3 Dysregulation of KLHL3 is involved in the pathophysiology of type 2 diabetes. These data offer a rationale for use of thiazide in individuals with diabetes and provide insights into the mechanism for cardiorenal protective effects of SGLT2 inhibitors.
Sections du résumé
BACKGROUND
Mechanisms underlying the frequent association between salt-sensitive hypertension and type 2 diabetes remain obscure. We previously found that protein kinase C (PKC) activation phosphorylates Kelch-like 3 (KLHL3), an E3 ubiquitin ligase component, at serine 433. We investigated whether impaired KLHL3 activity results in increased renal salt reabsorption
METHODS
We used the db/db diabetes mouse model to explore KLHL3's role in renal salt handling in type 2 diabetes and evaluated mechanisms of KLHL3 dysregulation in cultured cells.
RESULTS
We observed PKC activity in the db/db mouse kidney and phosphorylation of serine 433 in KLHL3 (KLHL3
CONCLUSIONS
Dysregulation of KLHL3 is involved in the pathophysiology of type 2 diabetes. These data offer a rationale for use of thiazide in individuals with diabetes and provide insights into the mechanism for cardiorenal protective effects of SGLT2 inhibitors.
Identifiants
pubmed: 30914436
pii: ASN.2018070703
doi: 10.1681/ASN.2018070703
pmc: PMC6493993
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Carrier Proteins
0
Glucosides
0
KLHL3 protein, mouse
0
Microfilament Proteins
0
Sodium-Glucose Transporter 2 Inhibitors
0
Solute Carrier Family 12, Member 3
0
Thiophenes
0
ipragliflozin
3N2N8OOR7X
WNK Lysine-Deficient Protein Kinase 1
EC 2.7.11.1
Protein Kinase C
EC 2.7.11.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
782-794Informations de copyright
Copyright © 2019 by the American Society of Nephrology.
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