Plasmin and Sodium Retention in Nephrotic Syndrome

Kleyman, Thomas R.; Hughey, Rebecca P.

doi:10.1681/asn.2008121236

Cited by 6 publications

(8 citation statements)

References 14 publications

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“…10,11 However, a definitive experimental proof from a genetic mouse model lacking plasminogen was pending. 19 In this study we confirm that urine from nephrotic nphs2 Δipod mice also contained large amounts of plasminogen and active plasmin as previously shown to be the case in mice with doxorubicin-induced nephrotic syndrome. 4 By generating nphs2 Δipod *plg −/− mice, we were able to provide further evidence on the role of plasminogen in ENaC-mediated sodium retention in experimental NS.…”

Section: Discussionsupporting

confidence: 88%

“…More direct evidence could be provided by a plg knockout model. 19 In two recent studies, our group followed the approach of utilizing knockout mouse models to define the in vivo role of the serine proteases plasma kallikrein (klkb1 −/− ) 20 and urokinase-type plasminogen activator (uPA −/− ) 9 in ENaC-mediated sodium retention in experimental NS. Both serine proteases were found to stimulate ENaC currents in vitro; however, the lack of either one did not protect nephrotic mice from ENaC-mediated sodium retention.…”

Section: Introductionmentioning

confidence: 99%

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Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome

et al. 2020

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Aim Sodium retention is the hallmark of nephrotic syndrome (NS) and mediated by the proteolytic activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases. Plasmin is highly abundant in nephrotic urine and has been proposed to be the principal serine protease responsible for ENaC activation in NS. However, a proof of the essential role of plasmin in experimental NS is lacking. Methods We used a genetic mouse model of NS based on an inducible podocin knockout (Bl6‐Nphs2tm3.1Antc*Tg(Nphs1‐rtTA*3G)8Jhm*Tg(tetO‐cre)1Jaw or nphs2Δipod). These mice were crossed with plasminogen deficient mice (Bl6‐Plgtm1Jld or plg−/−) to generate double knockout mice (nphs2Δipod*plg−/−). NS was induced after oral doxycycline treatment for 14 days and mice were followed for subsequent 14 days. Results Uninduced nphs2Δipod*plg−/− mice had normal kidney function and sodium handling. After induction, proteinuria increased similarly in both nphs2Δipod*plg+/+ and nphs2Δipod*plg−/− mice. Western blot revealed the urinary excretion of plasminogen and plasmin in nphs2Δipod*plg+/+ mice which were absent in nphs2Δipod*plg−/− mice. After the onset of proteinuria, amiloride‐sensitive natriuresis was increased compared to the uninduced state in both genotypes. Subsequently, urinary sodium excretion dropped in both genotypes leading to an increase in body weight and development of ascites. Treatment with the serine protease inhibitor aprotinin prevented sodium retention in both genotypes. Conclusions This study shows that mice lacking urinary plasminogen are not protected from ENaC‐mediated sodium retention in experimental NS. This points to an essential role of other urinary serine proteases in the absence of plasminogen.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome

et al. 2020

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“…Chronic but mild hypervolemia and hypertension could be the long-term consequences of reduced sodium excretion [29], and this may explain the comparatively higher systolic blood pressure in normotensive patients with positive family history of hypertension who are at a higher risk of developing high blood pressure. This defect of sodium excretion has also been used to explain the pathogenesis of the nephrotic syndrome [30, 31]. Contrary to earlier studies in which chloride was thought to play as much a role in hypertension as sodium [32-34], the 24-hour urinary chloride did not differ significantly in the present study groups.…”

Section: Discussioncontrasting

confidence: 80%

Increased urinary sodium excretion is associated with systolic blood pressure in first degree relatives of hypertensive patients in Ibadan, Southwestern Nigeria

Ajayi¹,

Adebiyi²,

Kadiri³

2018

Pan Afr Med J

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Introduction Understanding the risk factors of hypertension has led to a better understanding of the pathogenesis, prevention and reduction in morbidity of hypertension. It is well known that offsprings of hypertensive parents have an increased risk of developing hypertension. It is therefore necessary to explore the physiological differences between normotensive patients with and without a positive family history of hypertension with respect to their urinary excretion of sodium. Methods This study was carried out at the University College Hospital, Ibadan Nigeria, to determine if normotensive patients with a positive family history of hypertension are different with respect to their urinary excretion of electrolytes and blood pressure. It examined the relationship between 24-hour urinary excretion of sodium, chloride and potassium, urea and creatinine and blood pressure in subjects with and without family history of hypertension. It was a case-control study of sixty-two subjects: normotensive patients’ first degree relatives of primary hypertensive patients and normotensive patients without positive family history. Results The mean (SD) systolic blood pressures for subjects with and without family history of hypertension were significantly different: 120.0(22.25) and 105.0(17.50) respectively, (p=0.001). The mean arterial blood pressures were significantly different: 86.4(10.2) mmHg and 80.1(8.1) mmHg respectively (p=0.010). The mean (SD) 24-hour urinary excretion of sodium for normotensive patients with and without positive family history of hypertension were 180.5 (45.50) mEq/L, and 156.0(36.25) mEq/L respectively. Systolic blood pressure and 24-hour urinary excretion of sodium was also higher in normotensive subjects with a positive family history of hypertension. Conclusion Systolic blood pressure and twenty-four hour urinary excretion of sodium were higher in normotensive subjects with a positive family history of hypertension than in those without a family history of hypertension.

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“…Recently, we and others reported that plasmin can proteolytically activate ENaC heterologously expressed in Xenopus laevis oocytes (Passero et al, 2008; Svenningsen et al, 2009a). This suggests that ENaC activation by plasmin may contribute to renal sodium retention in nephrotic syndrome (Kleyman and Hughey, 2009; Passero et al, 2010; Svenningsen et al, 2012).…”

Section: Introductionmentioning

confidence: 97%

Plasmin and chymotrypsin have distinct preferences for channel activating cleavage sites in the γ subunit of the human epithelial sodium channel

Haerteis

Krappitz

Diakov

et al. 2012

Journal of General Physiology

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Proteolytic activation of the epithelial sodium channel (ENaC) involves cleavage of its γ subunit in a critical region targeted by several proteases. Our aim was to identify cleavage sites in this region that are functionally important for activation of human ENaC by plasmin and chymotrypsin. Sequence alignment revealed a putative plasmin cleavage site in human γENaC (K189) that corresponds to a plasmin cleavage site (K194) in mouse γENaC. We mutated this site to alanine (K189A) and expressed human wild-type (wt) αβγENaC and αβγK189AENaC in Xenopus laevis oocytes. The γK189A mutation reduced but did not abolish activation of ENaC whole cell currents by plasmin. Mutating a putative prostasin site (γRKRK178AAAA) had no effect on the stimulatory response to plasmin. In contrast, a double mutation (γRKRK178AAAA;K189A) prevented the stimulatory effect of plasmin. We conclude that in addition to the preferential plasmin cleavage site K189, the putative prostasin cleavage site RKRK178 may serve as an alternative site for proteolytic channel activation by plasmin. Interestingly, the double mutation delayed but did not abolish ENaC activation by chymotrypsin. The time-dependent appearance of cleavage products at the cell surface nicely correlated with the stimulatory effect of chymotrypsin on ENaC currents in oocytes expressing wt or double mutant ENaC. Delayed proteolytic activation of the double mutant channel with a stepwise recruitment of so-called near-silent channels was confirmed in single-channel recordings from outside-out patches. Mutating two phenylalanines (FF174) in the vicinity of the prostasin cleavage site prevented proteolytic activation by chymotrypsin. This indicates that chymotrypsin preferentially cleaves at FF174. The close proximity of FF174 to the prostasin site may explain why mutating the prostasin site impedes channel activation by chymotrypsin. In conclusion, this study supports the concept that different proteases have distinct preferences for certain cleavage sites in γENaC, which may be relevant for tissue-specific proteolytic ENaC activation.

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Plasmin and Sodium Retention in Nephrotic Syndrome

Cited by 6 publications

References 14 publications

Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome

Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome

Increased urinary sodium excretion is associated with systolic blood pressure in first degree relatives of hypertensive patients in Ibadan, Southwestern Nigeria

Plasmin and chymotrypsin have distinct preferences for channel activating cleavage sites in the γ subunit of the human epithelial sodium channel

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