{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nKelch‐like protein 3 (KLHL3) functions as a key adaptor protein in an E3 ubiquitin ligase complex that targets with‐no‐lysine kinases (WNK1, WNK4) and other substrates for ubiquitin‐mediated degradation. This regulation is essential for proper salt and potassium homeostasis in the kidney, where the degradation of these kinases prevents overactivation of the downstream OSR1/SPAK–NaCl cotransporter (NCC) cascade. When KLHL3 function is impaired, as in various genetic mutations, increased levels of WNK kinases lead to enhanced NCC phosphorylation, ultimately manifesting as pseudohypoaldosteronism type II (PHAII) characterized by salt‐sensitive hypertension, hyperkalemia, and metabolic acidosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to controlling WNK kinase abundance, KLHL3 is intricately involved in fine‐tuning renal electrolyte transport through multiple mechanisms. Specific mutations in KLHL3 (in domains such as the Kelch repeat or BTB domains) not only disrupt the binding to either WNK kinases or its E3 scaffold partner Cullin3 but can also lead to a dominant negative effect through aberrant dimerization. Moreover, KLHL3 directly binds alternative substrates such as claudin‑8 in the collecting duct to modulate paracellular chloride permeability. The regulatory network is further modulated by dietary signals; for example, low‐potassium intake induces protein kinase C–mediated phosphorylation of KLHL3 that impairs substrate binding, leading to increased WNK4 accumulation and NCC activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther studies have highlighted additional complexities in KLHL3 biology. For instance, the ubiquitin ligase complex differentially affects full‐length versus kidney‐specific isoforms of WNK1, and mutations preferentially impairing degradation of the KS‐WNK1 isoform evoke milder clinical phenotypes. Beyond its classical role in the distal nephron, KLHL3 dysfunction has been linked to extrarenal effects such as altered energy expenditure in the liver, which may mitigate obesity and insulin resistance. Animal models mimicking various KLHL3 mutations recapitulate the key features of familial hyperkalemic hypertension and underline the indispensability of proper KLHL3–Cullin3 interaction for maintaining electrolyte balance and blood pressure."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Koichiro Susa, Eisei Sohara, Tatemitsu Rai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu217"}], "href": "https://doi.org/10.1093/hmg/ddu217"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24821705"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24821705"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yongfeng Gong, Jinzhi Wang, Jing Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "KLHL3 regulates paracellular chloride transport in the kidney by ubiquitination of claudin-8."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1421441112"}], "href": "https://doi.org/10.1073/pnas.1421441112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25831548"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25831548"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kenichi Ishizawa, Ning Xu, Johannes Loffing, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Potassium depletion stimulates Na-Cl cotransporter "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "via"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2016.10.127"}], "href": "https://doi.org/10.1016/j.bbrc.2016.10.127"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27942049"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27942049"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Emi Sasaki, Koichiro Susa, Takayasu Mori, et al. "}, {"type": "b", "children": [{"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "KLHL3"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00508-16"}], "href": "https://doi.org/10.1128/MCB.00508-16"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28052936"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28052936"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Koichiro Susa, Eisei Sohara, Daiei Takahashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WNK4 is indispensable for the pathogenesis of pseudohypoaldosteronism type II caused by mutant KLHL3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2017.07.121"}], "href": "https://doi.org/10.1016/j.bbrc.2017.07.121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28743496"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28743496"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sayaka Yoshida, Yuya Araki, Takayasu Mori, et al. 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