Sodium Retention and Volume Expansion in Nephrotic Syndrome: Implications for Hypertension

Ray, Evan C.; Rondon‐Berrios, Helbert; Boyd, Cary R.; Kleyman, Thomas R.

doi:10.1053/j.ackd.2014.11.006

Cited by 60 publications

(61 citation statements)

References 91 publications

(97 reference statements)

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“…Augmented ENaC activity also results from proteolytic processing of the large extracellular domain of α‐ and γENaC. A dual cleavage event in either subunit releases small intrinsic inhibitory tracts transitioning channels to a more active state . While furin, an endogenous protease, was shown to cleave αENaC twice, it cleaves the γENaC only once.…”

Section: Introductionmentioning

confidence: 99%

Cathepsin B increases ENaC activity leading to hypertension early in nephrotic syndrome

Larionov

Dahlke

Kunke

et al. 2019

J Cellular Molecular Medi

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The NPHS2 gene, encoding the slit diaphragm protein podocin, accounts for genetic and sporadic forms of nephrotic syndrome (NS). Patients with NS often present symptoms of volume retention, such as oedema formation or hypertension. The primary dysregulation in sodium handling involves an inappropriate activation of the epithelial sodium channel, ENaC. Plasma proteases in a proteinuria‐dependent fashion have been made responsible; however, referring to the timeline of symptoms occurring and underlying mechanisms, contradictory results have been published. Characterizing the mouse model of podocyte inactivation of NPHS2 (Nphs2∆pod) with respect to volume handling and proteinuria revealed that sodium retention, hypertension and gross proteinuria appeared sequentially in a chronological order. Detailed analysis of Nphs2∆pod during early sodium retention, revealed increased expression of full‐length ENaC subunits and αENaC cleavage product with concomitant increase in ENaC activity as tested by amiloride application, and augmented collecting duct Na+/K+‐ATPase expression. Urinary proteolytic activity was increased and several proteases were identified by mass spectrometry including cathepsin B, which was found to process αENaC. Renal expression levels of precursor and active cathepsin B were increased and could be localized to glomeruli and intercalated cells. Inhibition of cathepsin B prevented hypertension. With the appearance of gross proteinuria, plasmin occurs in the urine and additional cleavage of γENaC is encountered. In conclusion, characterizing the volume handling of Nphs2∆pod revealed early sodium retention occurring independent to aberrantly filtered plasma proteases. As an underlying mechanism cathepsin B induced αENaC processing leading to augmented channel activity and hypertension was identified.

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Section: Introductionmentioning

confidence: 99%

Cathepsin B increases ENaC activity leading to hypertension early in nephrotic syndrome

Larionov

Dahlke

Kunke

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…Two major hypotheses have been proposed to explain edema formation, the underfill and overfill theory, respectively, which have been recently reviewed (Ellis ; Hoorn and Ellison ; Ray et al. ; Teoh et al. ).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the overfill mechanism is based on proteolytically activated hyperactive ENaC channels as reviewed by Ray et al. ().…”

Section: Introductionmentioning

confidence: 99%

Amiloride resolves resistant edema and hypertension in a patient with nephrotic syndrome; a case report

et al. 2018

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Sodium and fluid retention is a hallmark and a therapeutic challenge of the nephrotic syndrome (NS). Studies support the “overfill” theory of NS with pathophysiological proteolytic activation of the epithelial sodium channel (ENaC) which explains the common observation of suppressed renin –angiotensin system and poor therapeutic response to ACE inhibitors. Blockade of ENaC by the diuretic amiloride would be a rational intervention compared to the traditionally used loop diuretics. We describe a 38‐year‐old male patient with type1 diabetes who developed severe hypertension (200/140 mmHg), progressive edema (of at least 10 L), and overt proteinuria (18.5 g/24 h), despite combined administration of five antihypertensive drugs. Addition of amiloride (5 mg/day) to treatment resulted in resolution of edema, weight loss of 7 kg, reduction in blood pressure (150/100–125/81 mmHg), increased 24 h urinary sodium excretion (127–165 mmol/day), decreased eGFR (41–29 mL/min), and increased plasma potassium concentration (4.6–7.8 mmol/L). Blocking of ENaC mobilizes nephrotic edema and lowers blood pressure in NS. However, acute kidney injury and dangerous hyperkalemia is a potential risk if amiloride is added to multiple other antihypertensive medications as ACEi and spironolactone. The findings support that ENaC is active in NS and is a relevant target in adult NS patients.

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“…Loss of the inhibitory tract increases the channel's open probability (Ray et al. ). A host of other secondary proteases, if present, could also perform this role and activate ENaC.…”

mentioning

confidence: 99%

Sodium Retention and Volume Expansion in Nephrotic Syndrome: Implications for Hypertension

Cited by 60 publications

References 91 publications

Cathepsin B increases ENaC activity leading to hypertension early in nephrotic syndrome

Cathepsin B increases ENaC activity leading to hypertension early in nephrotic syndrome

Amiloride resolves resistant edema and hypertension in a patient with nephrotic syndrome; a case report

ENaC blockade in proteinuria-associated extracellular fluid volume overload - effective but risky

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