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10.1681/ASN.2014070728

http://scihub22266oqcxt.onion/10.1681/ASN.2014070728
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25967121!4696563!25967121
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suck abstract from ncbi


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pmid25967121      J+Am+Soc+Nephrol 2016 ; 27 (1): 107-19
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  • Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na(+)-K(+)-2Cl(-) Cotransporter #MMPMID25967121
  • Borschewski A; Himmerkus N; Boldt C; Blankenstein KI; McCormick JA; Lazelle R; Willnow TE; Jankowski V; Plain A; Bleich M; Ellison DH; Bachmann S; Mutig K
  • J Am Soc Nephrol 2016[Jan]; 27 (1): 107-19 PMID25967121show ga
  • The furosemide-sensitive Na(+)-K(+)-2Cl(-)-cotransporter (NKCC2) is crucial for NaCl reabsorption in kidney thick ascending limb (TAL) and drives the urine concentrating mechanism. NKCC2 activity is modulated by N-terminal phosphorylation and dephosphorylation. Serine-threonine kinases that activate NKCC2 have been identified, but less is known about phosphatases that deactivate NKCC2. Inhibition of calcineurin phosphatase has been shown to stimulate transport in the TAL and the distal convoluted tubule. Here, we identified NKCC2 as a target of the calcineurin Abeta isoform. Short-term cyclosporine administration in mice augmented the abundance of phospho-NKCC2, and treatment of isolated TAL with cyclosporine increased the chloride affinity and transport activity of NKCC2. Because sorting-related receptor with A-type repeats (SORLA) may affect NKCC2 phosphoregulation, we used SORLA-knockout mice to test whether SORLA is involved in calcineurin-dependent modulation of NKCC2. SORLA-deficient mice showed more calcineurin Abeta in the apical region of TAL cells and less NKCC2 phosphorylation and activity compared with littermate controls. In contrast, overexpression of SORLA in cultured cells reduced the abundance of endogenous calcineurin Abeta. Cyclosporine administration rapidly normalized the abundance of phospho-NKCC2 in SORLA-deficient mice, and a functional interaction between calcineurin Abeta and SORLA was further corroborated by binding assays in rat kidney extracts. In summary, we have shown that calcineurin Abeta and SORLA are key components in the phosphoregulation of NKCC2. These results may have clinical implications for immunosuppressive therapy using calcineurin inhibitors.
  • |Animals[MESH]
  • |Calcineurin/*physiology[MESH]
  • |Kidney/*metabolism[MESH]
  • |Male[MESH]
  • |Membrane Transport Proteins/*physiology[MESH]
  • |Mice[MESH]
  • |Phosphorylation[MESH]
  • |Rats[MESH]
  • |Rats, Sprague-Dawley[MESH]
  • |Receptors, LDL/*physiology[MESH]


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