Distal potassium handling based on flow modulation of maxi-K channel activity

Abstract

Purpose of review: Studies on the mechanisms of distal K+ secretion have highlighted the importance of the renal outer-medullary K+ (ROMK) and maxi-K channels. This review considers several human disorders characterized by hypokalemia and hyperkalemia, as well as mouse models of these disorders, and the mechanisms by which ROMK and maxi-K may be dysregulated.

Recent findings: Analysis of knockout mice lacking ROMK, a model for type II Bartter's syndrome, has shown a role for maxi-K in distal K+ secretion. Knockout mice lacking either the alpha or beta1 subunits of maxi-K also show deficits in flow-dependent K+ secretion. Analysis of transgenic and knock-in mouse models of pseudohypoaldosteronism type II, in which mutant forms of with-no-lysine kinase 4 are expressed, suggests ways in which ROMK and maxi-K may be dysregulated to result in hyperkalemia. Modeling studies also provide insights into the role of Na+ delivery vs. flow in K+ secretion.

Summary: The importance of both ROMK and maxi-K to distal K+ secretion is now well established, but the relative role that each of these two channels plays in normal and diseased states has not been definitively established. Analysis of human and animal model data can generate hypotheses for future experiments.

Figure 1. Flow-dependent increase in K⁺ secretion involves both ROMK and Maxi-K

Decreases or loss of function of NKCC2 or NCC increase fluid and Na⁺ delivery to CNT, the key site for K⁺ secretion. Increased fluid flow decreases luminal K⁺ concentration. Increased Na⁺ delivery increases Na⁺ reabsorption via ENaC and depolarizes apical membrane potential (indicated by “+Vm”). Both factors increase K⁺ secretion via ROMK and maxi-K. In addition, increased fluid flow stimulates Ca²⁺ entry to activate maxi-K. Thus, both ROMK and maxi-K contribute to flow-dependent K⁺ secretion at the low flow rate. The relative contribution by maxi-K is increased at the high flow rate. Maxi-K is also activated by membrane depolarization. The contribution from membrane polarization due to increased ENaC activity to the activation of maxi-K, however, is relatively small compared to that from increases in fluid flow and the rise in intracellular Ca²⁺ concentration. See text for abbreviations.

Figure 2. Three potential mechanisms for hyperkalemia in patients of PHA2 with WNK4 mutations

First, overactivity of NCC decreases Na⁺ reabsorption via ENaC, hyperpolarizes membrane potential (indicated by “-Vm”), and decreases K⁺ efflux via ROMK and maxi-K. Second, mutations in WNK4 that cause PHA2 inhibit ROMK by increasing its endocytosis (indicated by “En”). Third, reduced fluid flow to CNT decreases the opening of maxi-K. Because hyperkalemia causes upregulation of ROMK and maxi-K, the increase in the endocytosis of ROMK and “functional” inhibition of maxi-K (i.e., secondary to reduced Na⁺ and fluid delivery) are likely critical for sustained hyperkalemia.

Figure 3. Hypothetical model for steady-state tubular Na⁺ handling in PHA2 patients with WNK4 mutations

It is assumed that WNK4 mutations increase Na⁺ reabsorption in DCT from 6% (of filtered load) in control to 12% in the diseased state. Assuming that the compensatory decrease in Na⁺ reabsorption (in response to volume expansion and hypertension) occurs in the tubular segments proximal as well as distal to DCT, Na⁺ delivery to the CNT/CD will be reduced compared to the control (2% vs 4% in PHA2 vs control, respectively). It should be mentioned that the axial fluid profile does not parallel that for Na⁺ delivery because DCT lacks aquaporin-2.