{"doi":"10.34067/kid.0005752022","title":"Potassium Homeostasis and WNK Kinases in the Regulation of the Sodium-Chloride Cotransporter: Hyperaldosteronism and Its Metabolic Consequences","abstract":"Shortly after the discovery of aldosterone (1), Jerome Conn and colleagues characterized a form of hypertension, indelibly associated with Conn’s name, that exhibited excessive aldosterone production for the degree of sodium (Na+) intake, severe hypertension, hypokalemia, and metabolic alkalosis (2). Primary hyperaldosteronism continues to be a major cause of hypertension, with a greater degree of risk for cardiovascular complications than can be attributed to the severity of hypertension (3). An important element of this increased risk is persistent, and inappropriate, mineralocorticoid receptor (MR) activation and its attendant consequences; these consequences include effects on many organs, including the heart, vasculature, kidney, liver, skeletal muscle, and adipocytes. Common burdens of MR activation include increased oxidative stress, inflammation, and insulin resistance that weigh heavily on all organs, but cardiac fibrosis and hypertrophy, vascular endothelial dysfunction, renal podocyte dysfunction, and proteinuria are particularly pernicious to the cardiorenal axis (4). Whether this greater risk reflects these other metabolic effects of hyperaldosteronism, the frequent occurrence of hypokalemia or metabolic alkalosis, or a combination of these factors, is not clear. Although hypokalemia is frequently present in hyperaldosteronism, the use of the aldosterone/renin ratio as a screening test has expanded the recognition that primary hyperaldosteronism without hypokalemia is not so rare as early studies proposed and represents a substantial percentage of patients with refractory or severe hypertension (5,6). However, the presence of hypokalemia typically exacerbates the severity of hypertension in hyperaldosteronism and is associated with a more severe disease progression (7). The adverse cardiovascular and renal effects of hypokalemia, and low potassium (K+) diets in general, are well known (8910–11). Conversely, diets rich in K+ have been shown to reduce systemic BP and improve hypertension, slow the decline of renal function, and lower the incidence of cardiovascular complications (1112131415161718–19). Part of the benefit of K+-rich diets is attributed to their natriuretic effect (20,21). Reduced dietary K+ content promotes Na+ retention, whereas K+ supplementation has the opposite effect. Because low-K+ diets reduce aldosterone production, their effect normally supersedes aldosterone’s action to cause Na+ retention (9,22). In contrast, K+ supplementation reduces mineralocorticoid-induced Na+ retention and hypertension (4,232425262728293031–32). K+ depletion, in addition to promoting sodium chloride (NaCl) retention, consistently causes an increase in renal vascular resistance (33,34), which predisposes to salt-sensitive hypertension (24). Structurally, the earliest renal changes occur in the outer medullary collecting duct (3536–37), with net K+ absorption (3839–40), so that a portion of distal cortical net K+ secretion is reabsorbed (recycled) within the renal medulla (41,42). However, the degree of medullary K+ recycling increases during K+ loading (43), whereas two maneuvers that reduce net cortical K+ secretion (dietary K+ restriction and administration of amiloride) reduce K+ recycling (414243–44). Absorptive K+ efflux in the cortex also participates in the regulation of tubular net K+ transport (454647–48). Stokes (49) proposed that K+ recycling serves a physiologically important role to regulate medullary interstitial concentration, but data also indicate a role to modulate renal vascular resistance via tubuloglomerular feedback (50,51). One notable effect of hypokalemia is to phosphorylate and activate the thiazide-sensitive NaCl cotransporter, NCC (SLC12A3). This conclusion comes from the work of numerous investigators, and from the synthesis of genetic, physiologic, and biochemical studies that provide our current explanation for the role of aldosterone in NCC activation. Previous work identified that the ","journal":"Kidney360","year":2022,"id":296136,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9589,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":316129,"name":"Charles S. Wingo","orcid":null,"position":1,"is_corresponding":false},{"id":314942,"name":"Jermaine G. Johnston","orcid":"0000-0002-7509-6129","position":0,"is_corresponding":true}],"reference_count":107,"raw_metadata":null,"created_at":"2026-07-19T00:31:12.531553Z","pmid":"36514400","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}