Thiazide-Sensitive NaCl Cotransporter

2020 ◽  
pp. 57-92
Author(s):  
Arohan R. Subramanya
Keyword(s):  
Nacl Cotransporter

scholarly journals Effects of chemical chaperones on partially retarded NaCl cotransporter mutants associated with Gitelman's syndrome in a mouse cortical collecting duct cell line

2004 ◽  
Vol 19 (5) ◽  
pp. 1069-1076 ◽  
Author(s):  
J. C. de Jong ◽  
P. H. G. M. Willems ◽  
M. Goossens ◽  
A. Vandewalle ◽  
L. P. W. J. van den Heuvel ◽  
...  
Keyword(s):  
Cell Line ◽  
Collecting Duct ◽  
Duct Cell ◽  
Cortical Collecting Duct ◽  
Chemical Chaperones ◽  
Gitelman's Syndrome ◽  
Nacl Cotransporter

Structure-function relationships in the renal NaCl cotransporter (NCC)

2019 ◽  
pp. 177-204
Author(s):  
Erika Moreno ◽  
Paola de los Heros ◽  
Consuelo Plata ◽  
Christopher Cutler ◽  
Antonio Vega-Mateos ◽  
...  
Keyword(s):  
Structure Function ◽  
Nacl Cotransporter

scholarly journals Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice

2019 ◽  
Vol 30 (5) ◽  
pp. 782-794 ◽  
Author(s):  
Kenichi Ishizawa ◽  
Qin Wang ◽  
Jinping Li ◽  
Ning Xu ◽  
Yoshikazu Nemoto ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cultured Cells ◽  
Sglt2 Inhibitor ◽  
Distal Convoluted Tubule ◽  
Protective Effects ◽  
Human Embryonic Kidney Cells ◽  
Sodium Glucose Cotransporter ◽  
Tubule Cells ◽  
Nacl Cotransporter

BackgroundMechanisms 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 via NaCl cotransporter (NCC).MethodsWe 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.ResultsWe observed PKC activity in the db/db mouse kidney and phosphorylation of serine 433 in KLHL3 (KLHL3S433-P). This modification prevents binding of with-no-lysine (WNK) kinases; however, total KLHL3 levels were decreased, indicating severely impaired KLHL3 activity. This resulted in WNK accumulation, activating NCC in distal convoluted tubules. Ipragliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, lowered PKC activity in distal convoluted tubule cells and reduced KLHL3S433-P and NCC levels, whereas the thiazolidinedione pioglitazone did not, although the two agents similarly reduced in blood glucose levels. We found that, in human embryonic kidney cells expressing KLHL3 and distal convoluted tubule cells, cellular glucose accumulation increased KLHL3S433-P levels through PKC. Finally, the effect of PKC inhibition in the kidney of db/db mice confirmed PKC’s causal role in KLHL3S433-P and NCC induction.ConclusionsDysregulation 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.

scholarly journals Protein Phosphatase 1 Inhibitor–1 Mediates the cAMP-Dependent Stimulation of the Renal NaCl Cotransporter

2019 ◽  
Vol 30 (5) ◽  
pp. 737-750 ◽  
Author(s):  
David Penton ◽  
Sandra Moser ◽  
Agnieszka Wengi ◽  
Jan Czogalla ◽  
Lena Lindtoft Rosenbaek ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Mdck Cells ◽  
Ex Vivo ◽  
Phosphorylation Site ◽  
Mouse Kidney ◽  
Protein Phosphatase 1 ◽  
Endocrine Disorders ◽  
Kidney Slices ◽  
Nacl Cotransporter ◽  
Stimulation Of

BackgroundA number of cAMP-elevating hormones stimulate phosphorylation (and hence activity) of the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT). Evidence suggests that protein phosphatase 1 (PP1) and other protein phosphatases modulate NCC phosphorylation, but little is known about PP1’s role and the mechanism regulating its function in the DCT.MethodsWe used ex vivo mouse kidney preparations to test whether a DCT-enriched inhibitor of PP1, protein phosphatase 1 inhibitor–1 (I1), mediates cAMP’s effects on NCC, and conducted yeast two-hybrid and coimmunoprecipitation experiments in NCC-expressing MDCK cells to explore protein interactions.ResultsTreating isolated DCTs with forskolin and IBMX increased NCC phosphorylation via a protein kinase A (PKA)–dependent pathway. Ex vivo incubation of mouse kidney slices with isoproterenol, norepinephrine, and parathyroid hormone similarly increased NCC phosphorylation. The cAMP-induced stimulation of NCC phosphorylation strongly correlated with the phosphorylation of I1 at its PKA consensus phosphorylation site (a threonine residue in position 35). We also found an interaction between NCC and the I1-target PP1. Moreover, PP1 dephosphorylated NCC in vitro, and the PP1 inhibitor calyculin A increased NCC phosphorylation. Studies in kidney slices and isolated perfused kidneys of control and I1-KO mice demonstrated that I1 participates in the cAMP-induced stimulation of NCC.ConclusionsOur data suggest a complete signal transduction pathway by which cAMP increases NCC phosphorylation via a PKA-dependent phosphorylation of I1 and subsequent inhibition of PP1. This pathway might be relevant for the physiologic regulation of renal sodium handling by cAMP-elevating hormones, and may contribute to salt-sensitive hypertension in patients with endocrine disorders or sympathetic hyperactivity.

A Novel Distal Convoluted Tubule‐Specific Tamoxifen‐Inducible Cre‐Recombinase Driven by the NaCl Cotransporter Gene

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1 ◽  
Author(s):  
Ryan J. Cornelius ◽  
Avika Sharma ◽  
Xiao-Tong Su ◽  
Andrew P. McMahon ◽  
David H. Ellison ◽  
...  
Keyword(s):  
Cre Recombinase ◽  
Distal Convoluted Tubule ◽  
Nacl Cotransporter

scholarly journals The European eel NCCβ encodes for an electroneutral NaCl cotransporter that is not sensitive to thiazide diuretics (1099.1)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Erika Moreno ◽  
Christopher Cutler ◽  
María Chávez‐Canales ◽  
Norma Vazquez ◽  
Gerardo Gamba
Keyword(s):  
European Eel ◽  
Thiazide Diuretics ◽  
Nacl Cotransporter
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