Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia.

Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia. Am J Physiol Renal Physiol. 2019 Jul 31;: Authors: Ferdaus MZ, Mukherjee A, Nelson JW, Blatt PJ, Miller LN, Terker A, Staub O, Lin DH, McCormick JA Abstract Hypomagnesemia is associated with reduced kidney function and life-threatening complications, and sustains hypokalemia. The distal convoluted tubule (DCT) determines final urinary Mg2+ excretion, and via activity of the Na+-Cl- cotransporter (NCC) also plays a key role in K+ homeostasis by metering Na+ delivery to distal segments. Little is known about the mechanisms by which plasma [Mg2+] regulates NCC activity, and how low plasma [Mg2+] and [K+] interact to modulate NCC activity. To address this we performed dietary manipulation studies in mice. Compared with normal diet, abundances of total NCC (tNCC) and phosphorylated NCC (pNCC) were lower following short-term (3 days) or long-term (14 days) dietary Mg2+ restriction. Altered NCC activation is unlikely to play a role since we also observed lower tNCC abundance in mice lacking the two NCC-activating kinases SPAK and OSR1 following Mg2+ restriction. The E3 ubiquitin-protein ligase NEDD4-2 regulates NCC abundance during dietary NaCl loading or K+ restriction. Mg2+ restriction did not lower tNCC abundance in inducible nephron-specific NEDD4-2 knockout mice. tNCC and pNCC abundances were similar following short-term Mg2+ or combined Mg2+-K+ restriction, but ...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research

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