Patients with hypokalemia develop WNK bodies in the distal convoluted tubule of the kidney

Thomson, Martin N.; Schneider, Wolfgang; Mutig, Kerim; Ellison, David H.; Kettritz, Ralph; Bachmann, S.

doi:10.1152/ajprenal.00464.2018

Cited by 18 publications

(11 citation statements)

References 30 publications

(35 reference statements)

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“…To explore the possibility that WNK bodies might represent a step toward degradation of excessively produced NCCactivating kinases, we tested the localization of the aggresomal proteins HDAC6, vimentin, and aggresomal/autophagosomal protein p62 in mice fed the HS/LK diet. All three products were not detected in WNK bodies, which is in contrast with our previous documentation of HDAC6 in WNK bodies of patients with hypokalemia (31). Therefore, species-related differences in WNK body composition are possible.…”

Section: Discussioncontrasting

confidence: 99%

WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia

Thomson

Cuevas

Bewarder

et al. 2020

American Journal of Physiology-Renal Physiology

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K+ deficiency stimulates renal salt reuptake via the Na+-Cl− cotransporter (NCC) of the distal convoluted tubule (DCT), thereby reducing K+ losses in downstream nephron segments while increasing NaCl retention and blood pressure. NCC activation is mediated by a kinase cascade involving with no lysine (WNK) kinases upstream of Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1). In K+ deficiency, WNKs and SPAK/OSR1 concentrate in spherical cytoplasmic domains in the DCT termed “WNK bodies,” the significance of which is undetermined. By feeding diets of varying salt and K+ content to mice and using genetically engineered mouse lines, we aimed to clarify whether WNK bodies contribute to WNK-SPAK/OSR1-NCC signaling. Phosphorylated SPAK/OSR1 was present both at the apical membrane and in WNK bodies within 12 h of dietary K+ deprivation, and it was promptly suppressed by K+ loading. In WNK4-deficient mice, however, larger WNK bodies formed, containing unphosphorylated WNK1, SPAK, and OSR1. This suggests that WNK4 is the primary active WNK isoform in WNK bodies and catalyzes SPAK/OSR1 phosphorylation therein. We further examined mice carrying a kidney-specific deletion of the basolateral K+ channel-forming protein Kir4.1, which is required for the DCT to sense plasma K+ concentration. These mice displayed remnant mosaic expression of Kir4.1 in the DCT, and upon K+ deprivation, WNK bodies developed only in Kir4.1-expressing cells. We postulate a model of DCT function in which NCC activity is modulated by plasma K+ concentration via WNK4-SPAK/OSR1 interactions within WNK bodies.

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Section: Discussioncontrasting

confidence: 99%

WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia

Thomson

Cuevas

Bewarder

et al. 2020

American Journal of Physiology-Renal Physiology

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“…Of interest, the effects of K ϩ restriction on WNKs result in the formation of discrete and membrane-lacking foci in the DCT cytosol called "WNK bodies" (FIGURE 5B) (32). These WNK bodies have recently also been identified in human kidney biopsies of patients with chronic hypokalemic nephropathy (FIGURE 5C) (321).…”

Section: No Ncc Dephosphorylationmentioning

confidence: 99%

“…The pathogenesis of kaliopenic nephropathy is incompletely understood because some patients with chronic hypokalemia rarely develop CKD (Gitelman syndrome, distal renal tubular acidosis), whereas others do (Bartter syndrome, eating disorders, laxative abuse) (360). Of interest, in kidney biopsies of patients with chronic hypokalemic nephropathy, the response of the renal tubules to K ϩ deficiency is detectable in kidney biopsies as "WNK bodies" (FIGURE 5C) (321).…”

mentioning

confidence: 99%

Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis

Hoorn

Gritter

Cuevas³

et al. 2020

Physiological Reviews

118

137

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Daily dietary potassium (K+) intake may be as large as the extracellular K+ pool. To avoid acute hyperkalemia, rapid removal of K+ from the extracellular space is essential. This is achieved by translocating K+ into cells and increasing urinary K+ excretion. Emerging data now indicate that the renal thiazide-sensitive NaCl cotransporter (NCC) is critically involved in this homeostatic kaliuretic response. This suggests that the early distal convoluted tubule (DCT) is a K+ sensor that can modify sodium (Na+) delivery to downstream segments to promote or limit K+ secretion. K+ sensing is mediated by the basolateral K+ channels Kir4.1/5.1, a capacity that the DCT likely shares with other nephron segments. Thus, next to K+-induced aldosterone secretion, K+ sensing by renal epithelial cells represents a second feedback mechanism to control K+ balance. NCC’s role in K+ homeostasis has both physiological and pathophysiological implications. During hypovolemia, NCC activation by the renin-angiotensin system stimulates Na+ reabsorption while preventing K+ secretion. Conversely, NCC inactivation by high dietary K+ intake maximizes kaliuresis and limits Na+ retention, despite high aldosterone levels. NCC activation by a low-K+ diet contributes to salt-sensitive hypertension. K+-induced natriuresis through NCC offers a novel explanation for the antihypertensive effects of a high-K+ diet. A possible role for K+ in chronic kidney disease is also emerging, as epidemiological data reveal associations between higher urinary K+ excretion and improved renal outcomes. This comprehensive review will embed these novel insights on NCC regulation into existing concepts of K+ homeostasis in health and disease.

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“…Among these changes, especially a serious decrease in potassium has been revealed by studies. Although the mechanism of hypokalaemia that occurs after potassium loss leads to kidney disease is not clear, it is histologically associated with vacuolization [28,29]. In our study, a statistically signi cant increase was found in Exercise group compared to Control group in the assessment for vacuolization.…”

Section: Discussionmentioning

confidence: 39%

The Effects of Branched Chain Amino Acid Supplement on Kidney Tissue of Exercising Rats

Aydeğer¹,

Eroğlu²

2021

Preprint

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One of the supplements used in with exercise programs is branched chain amino acids (BCAAs) which preferred because of their effect on novation of muscle protein synthesis. However, BCAAs increase their amount in the blood in a short time due to their properties. In this case, the result can increase the workload of the kidneys. Based on the information, this study investigated the effects of resistance exercise and BCAA supplements on kidney tissue. A total of 24 Wistar Albino male rats were divided equally into 4 groups: Control, BCAA, Exercise and Exercise+BCAA. In six-week study, resistance swimming exercise was applied to exercise groups. BCAA groups were given BCAA supplements at doses of 2.5 mg/kg before exercise. End of the study, histological, immunochemical, and RT-PCR analyses were performed. As a result of the findings obtained, it was found that use of BCAA supplements together with exercise caused tubular necrosis (p=0.002). A significant increase was found in caspase 3 IHC staining findings in BCAA and Exercise+BCAA groups compared to Control group (p=0.011; p=0.02). Also, KIM-1 expression levels were higher in Exercise group compared to all other groups (p=0.004; p=0.003; p=0.008). As a result, BCAA consumption in combination with resistant exercise caused damage to kidney tissue.

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Patients with hypokalemia develop WNK bodies in the distal convoluted tubule of the kidney

Cited by 18 publications

References 30 publications

WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia

WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia

Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis

The Effects of Branched Chain Amino Acid Supplement on Kidney Tissue of Exercising Rats

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