Mechanisms coupling sodium and magnesium reabsorption in the distal convoluted tubule of the kidney.

Gijs A C Franken,Anastasia Adella,Jeroen H F De Baaij,René J M Bindels

doi:10.1111/apha.13528

Gijs A C Franken, Anastasia Adella + Show 2 more

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https://doi.org/10.1111/apha.13528

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Abstract

Hypomagnesaemia is a common feature of renal Na+ wasting disorders such as Gitelman and EAST/SeSAME syndrome. These genetic defects specifically affect Na+ reabsorption in the distal convoluted tubule, where Mg2+ reabsorption is tightly regulated. Apical uptake via TRPM6 Mg2+ channels and basolateral Mg2+ extrusion via a putative Na+‐Mg2+ exchanger determines Mg2+ reabsorption in the distal convoluted tubule. However, the mechanisms that explain the high incidence of hypomagnesaemia in patients with Na+ wasting disorders of the distal convoluted tubule are largely unknown. In this review, we describe three potential mechanisms by which Mg2+ reabsorption in the distal convoluted tubule is linked to Na+ reabsorption. First, decreased activity of the thiazide‐sensitive Na+/Cl− cotransporter (NCC) results in shortening of the segment, reducing the Mg2+ reabsorption capacity. Second, the activity of TRPM6 and NCC are determined by common regulatory pathways. Secondary effects of NCC dysregulation such as hormonal imbalance, therefore, might disturb TRPM6 expression. Third, the basolateral membrane potential, maintained by the K+ permeability and Na+‐K+‐ATPase activity, provides the driving force for Na+ and Mg2+ extrusion. Depolarisation of the basolateral membrane potential in Na+ wasting disorders of the distal convoluted tubule may therefore lead to reduced activity of the putative Na+‐Mg2+ exchanger SLC41A1. Elucidating the interconnections between Mg2+ and Na+ transport in the distal convoluted tubule is hampered by the currently available models. Our analysis indicates that the coupling of Na+ and Mg2+ reabsorption may be multifactorial and that advanced experimental models are required to study the molecular mechanisms.

Highlights

The distal convoluted tubule (DCT) is an essential nephron segment for blood pressure regulation and potassium (K+) homeostasis
We present three hypotheses of mechanisms underlying the hypomagnesaemia caused by genetic DCT Na+ wasting disorders
Given that the Na+-K+-ATPase is crucial for the K+ recycling and thereby contributes to K+ permeability, its reduced activity in EAST/SeSAME and Gitelman syndrome will result in a depolarised basolateral membrane

Summary

| INTRODUCTION

The distal convoluted tubule (DCT) is an essential nephron segment for blood pressure regulation and potassium (K+) homeostasis. Insulin stimulates Na+ reabsorption in the kidney, as notoriously known by the increased risk of hypertension in diabetic type II patients.[123,124] Apart from increasing Na+ transport in the proximal tubule and loop of Henle,[125,126] insulin has be shown to both modulate NCC and TRPM6 activity by a PI3K (phosphoinositide 3 kinases), mTORC2 (mechanistic target of rapamycin complex 2) and AKT1 (AKT serine/threonine kinase 1)-dependent phosphorylation cascade (Figure 3).[5,6,10] impaired glucose metabolism and insulin resistance have been described in Gitelman patients,[127,128,129] the minor changes in plasma insulin levels make it unlikely that insulin is responsible for hypomagnesaemia in Na+ wasting disorders. Na+-K+-ATPase activity has never been directly assessed in Gitelman syndrome, data from thiazide-treated

Na-K-ATPase x ATP

Findings

| Conclusion and perspectives