TY  - JOUR
A1  - Mutig, Kerim
A1  - Kahl, Thomas
A1  - Saritas, Turgay
A1  - Godes, Michael
A1  - Persson, Pontus
A1  - Bates, James
A1  - Raffi, Hajamohideen
A1  - Rampoldi, Luca
A1  - Uchida, Shinichi
A1  - Hille, Carsten
A1  - Dosche, Carsten
A1  - Kumar, Satish
A1  - Castaneda-Bueno, Maria
A1  - Gamba, Gerardo
A1  - Bachmann, Sebastian
T1  - Activation of the Bumetanide-sensitive Na+, K+,2Cl(-) Cotransporter (NKCC2) Is Facilitated by Tamm-Horsfall Protein in a Chloride-sensitive Manner
JF  - The journal of biological chemistry
N2  - Active transport of NaCl across thick ascending limb (TAL) epithelium is accomplished by Na+, K+,2Cl(-) cotransporter (NKCC2). The activity of NKCC2 is determined by vasopressin (AVP) or intracellular chloride concentration and includes its amino-terminal phosphorylation. Co-expressed Tamm-Horsfall protein (THP) has been proposed to interact with NKCC2. We hypothesized that THP modulates NKCC2 activity in TAL. THP-deficient mice (THP-/-) showed an increased abundance of intracellular NKCC2 located in subapical vesicles (+47% compared with wild type (WT) mice), whereas base-line phosphorylation of NKCC2 was significantly decreased (-49% compared with WT mice), suggesting reduced activity of the transporter in the absence of THP. Cultured TAL cells with low endogenous THP levels and low base-line phosphorylation of NKCC2 displayed sharp increases in NKCC2 phosphorylation (+38%) along with a significant change of intracellular chloride concentration upon transfection with THP. In NKCC2-expressing frog oocytes, co-injection with THP cRNA significantly enhanced the activation of NKCC2 under low chloride hypotonic stress (+112% versus +235%). Short term (30 min) stimulation of the vasopressin V2 receptor pathway by V2 receptor agonist (deamino-cis-D-Arg vasopressin) resulted in enhanced NKCC2 phosphorylation in WT mice and cultured TAL cells transfected with THP, whereas in the absence of THP, NKCC2 phosphorylation upon deamino-cis-D-Arg vasopressin was blunted in both systems. Attenuated effects of furosemide along with functional and structural adaptation of the distal convoluted tubule in THP-/- mice supported the notion that NaCl reabsorption was impaired in TAL lacking THP. In summary, these results are compatible with a permissive role for THP in the modulation of NKCC2-dependent TAL salt reabsorptive function.
Y1  - 2011
U6  - https://doi.org/10.1074/jbc.M111.222968
SN  - 0021-9258
VL  - 286
IS  - 34
SP  - 30200
EP  - 30210
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Schildroth, Janice
A1  - Rettig-Zimmermann, Juliane
A1  - Kalk, Philipp
A1  - Steege, Andreas
A1  - Faehling, Michael
A1  - Sendeski, Mauricio
A1  - Paliege, Alexander
A1  - Lai, En Yin
A1  - Bachmann, Sebastian
A1  - Persson, Pontus B.
A1  - Hocher, Berthold
A1  - Patzak, Andreas
T1  - Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice
JF  - Nephrology, dialysis, transplantation
N2  - Background. Endothelin 1 contributes to renal blood flow control and pathogenesis of kidney diseases. The differential effects, however, of endothelin 1 (ET-1) on afferent (AA) and efferent arterioles (EA) remain to be established.
 Methods. We investigated endothelin type A and B receptor (ETA-R, ETB-R) functions in the control of AA and EA. Arterioles of ETB-R deficient, rescued mice [ETB (-/-)] and wild types [ETB(+/+)] were microperfused.
 Results. ET-1 constricted AA stronger than EA in ETB (-/-) and ETB(+/+) mice. Results in AA: ET-1 induced similar constrictions in ETB(-/-) and ETB(+/+) mice. BQ-123 (ETA-R antagonist) inhibited this response in both groups. ALA-ET-1 and IRL1620 (ETB-R agonists) had no effect on arteriolar diameter. L-NAME did neither affect basal diameters nor ET-1 responses. Results in EA: ET-1 constricted EA stronger in ETB(+/+) compared to ETB(-/-). BQ-123 inhibited the constriction completely only in ETB(-/-). ALA-ET-1 and IRL1620 constricted only arterioles of ETB(+/+) mice. L-NAME decreased basal diameter in ETB(+/+), but not in ETB(-/-) mice and increased the ET-1 response similarly in both groups. The L-NAME actions indicate a contribution of ETB-R in basal nitric oxide (NO) release in EA and suggest dilatory action of ETA-R in EA.
 Conclusions. ETA-R mediates vasoconstriction in AA and contributes to vasoconstriction in EA in this mouse model. ETB-R has no effect in AA but mediates basal NO release and constriction in EA. The stronger effect of ET-1 on AA supports observations of decreased glomerular filtration rate to ET-1 and indicates a potential contribution of ET-1 to the pathogenesis of kidney diseases.
KW  - endothelin
KW  - ETB receptor-deficient mouse
KW  - glomerular arterioles
KW  - renal haemodynamics
Y1  - 2011
U6  - https://doi.org/10.1093/ndt/gfq534
SN  - 0931-0509
VL  - 26
IS  - 3
SP  - 779
EP  - 789
PB  - Oxford Univ. Press
CY  - Oxford
ER  -