Monogenic Kidney Disorders as Hidden Drivers of Electrolyte Imbalance and Hypertension

Figures

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  Fig. 1. Physiological regulation of sodium transport in principal cells of the distal nephron and its dysregulation in Liddle syndrome. Under normal conditions, aldosterone binds to the MR, leading to increased transcription of ENaC subunits and SGK1. SGK1 enhances ENaC activity in part by inhibiting the E3 ubiquitin ligase NEDD4-2, which normally binds to the PY motif of ENaC subunits and promotes channel ubiquitination and internalization. This tightly regulated balance maintains appropriate sodium reabsorption. In Liddle syndrome, gain-of-function mutations in ENaC disrupt the PY motif, preventing NEDD4-2–mediated degradation and resulting in constitutive ENaC activation and sodium reabsorption independent of aldosterone. BK, large-conductance calcium-activated potassium channel; CD, collecting duct; ENaC, epithelial sodium channel; HRE, hormone response element; MR, mineralocorticoid receptor; NEDD4-2, neural precursor cell expressed developmentally down-regulated 4-2; ROMK, renal outer medullary potassium channel; SGK1, serum and glucocorticoid-regulated kinase 1.

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  Fig. 2. Mechanisms of Gordon syndrome. (A) In the DCT, activation of the WNK–SPAK/OSR1 signaling cascade increases the activity of the NCC, enhancing sodium and chloride reabsorption. Gain-of-function mutations in WNK1 or WNK4 increase WNK kinase activity, whereas loss-of-function mutations in CUL3 or KLHL3 impair ubiquitin-mediated degradation of WNK kinases, leading to their accumulation and sustained NCC activation. (B) Increased sodium reabsorption in the DCT reduces distal sodium delivery to the CD, thereby decreasing ENaC-mediated sodium uptake and impairing potassium secretion through apical potassium channels such as ROMK, resulting in hyperkalemia. CD, collecting duct; CUL3, Cullin 3; DCT, distal convoluted tubule; ENaC, epithelial sodium channel; KLHL3, Kelch-like protein 3; NCC, sodium–chloride cotransporter; OSR1, oxidative stress–responsive kinase 1; ROMK, renal outer medullary potassium channel; SPAK, SPS1-related proline/alanine-rich kinase; WNK, with-no-lysine (K) kinase.

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  Fig. 3. Mechanisms of apparent mineralocorticoid excess syndrome. In normal physiology, 11β-HSD2 converts cortisol to inactive cortisone, thereby protecting the MR from activation by cortisol. In apparent mineralocorticoid excess syndrome, deficiency of 11β-HSD2 permits cortisol to bind to and activate the MR in the distal nephron, mimicking a state of mineralocorticoid excess despite low circulating aldosterone levels. This results in increased ENaC activity, sodium retention, extracellular volume expansion, and suppression of the renin–angiotensin–aldosterone system. 11β-HSD2, 11β-hydroxysteroid dehydrogenase type 2; BK, large-conductance calcium-activated potassium channel; CD, collecting duct; ENaC, epithelial sodium channel; HRE, hormone response element; MR, mineralocorticoid receptor; NEDD4-2, neural precursor cell expressed developmentally down-regulated 4-2; ROMK, renal outer medullary potassium channel; SGK1, serum and glucocorticoid-regulated kinase 1.