http:/ / w w w.revistanefrologia.

com
sh or t re v ie w s 2011 Revista Nefrologa. Official Publication of the Spanish Nephrology Society

New insights into the pathophysiology of oedema

in nephrotic syndrome
H. Rondon-Berrios
Division of Nephrology. Department of Internal Medicine. University of New Mexico School of Medicine.
Albuquerque, New Mexico (USA)

Nefrologia 2011;31(2):148-54
doi:10.3265/Nefrologia.pre2010.Nov.10724

ABSTRACT Avances en la fisiopatologa del edema en el sndrome

nefrtico
O edema is a common clinical manifestation of nephrotic
RESUMEN
syndrome. Ho w ever, the pathophysiological mechanism of
sodium retention in nephrotic syndrome has been intensely El edema es una manifestacin clnica frecuente del sndrome
nefrtico (SN); sin embargo, el mecanismo fisiopatolgico
debated for decades. Several clinical and experimental obser-
responsable de la retencin de sodio ha sido un tema de
vations argue against the classic or " underfill " hypothesis of
intenso debate durante dcadas. M uchas observaciones
oedema formation in nephrotic syndrome. In many patients,
clnicas y experimentales no apoyan a la hiptesis clsica o del
oedema formation in nephrotic syndrome is due to the kid-
underfill en la formacin del edema nefrtico. En numerosos
ney being intrinsically unable to excrete salt and is unrelated pacientes, el edema propio del SN se produce por un defecto
to systemic factors (i.e. hypoalbuminaemia, decreased effec- renal intrnseco en la excrecin de sodio y es independiente
tive arterial blood volume, and secondary hyperaldostero- de factores sistmicos (p. ej., hipoalbuminemia, disminucin
nism). The cortical collecting duct is the nephron site of so- del volumen arterial efectivo o hiperaldosteronismo
dium retention in nephrotic syndrome. Activation of the secundario). El punto de la nefrona donde se produce la
epithelial sodium channel in the cortical collecting duct is res- retencin de sodio en el SN es el tbulo colector cortical. La
ponsible for sodium retention in nephrotic syndrome. In activacin del canal de sodio epitelial a ese nivel es
nephrotic syndrome, a defective glomerular filtration barrier responsable de la retencin de sodio en la patologa que nos
allo ws the passage of proteolytic enzymes or their precursors, ocupa. Una barrera glomerular defectuosa propia del SN
permitira el paso de enzimas proteolticas o sus precursores
w hich have the ability to activate the epithelial sodium chan-
que a su vez activaran el canal de sodio epitelial causando de
nel, thereby causing the the subsequent sodium retention
esa manera su retencin y consiguiente edema.
and oedema.
Keywords: Oedema. Nephrotic syndrome. Hypoalbuminemia. Palabras clave: Edema. Sndrome nefrtico. Hipoalbuminemia.
Epithelial sodium channel. Plasmin Canal epitelial de sodio. Plasmina.

INTRODUCTION

Oedema is defined as the accumulation of fluid in the has been under considerable debate for decades. The
interstitial space and is a frequent clinical manifestation of classic hypothesis, also called the underfill hypothesis,
nephrotic syndrome (NS). However, its pathophysiology postulates that sodium retention in NS is secondary to
decreased effective arterial blood volume, hence the term
underfill. The hypothesis suggests the following sequence
Correspondence: Helbert Rondon-Berrios of events (Figure 1): urinary loss of proteins in NS,
Division of Nephrology. Department of Internal Medicine.
especially albumin, causing hypoalbuminaemia, which
University of New Mexico School of Medicine, A C C 5. MSC10 5550.
1 University of New Mexico, 87131-0001. in turn causes a decrease in plasma oncotic pressure.
Albuquerque, New Mexico, USA. This decrease in plasma oncotic pressure would then
[email protected] cause an imbalance in Starling forces, resulting in the

148
H. Rondon-Berrios. O edema in nephrotic syndrome
sh or t re v ie w s

retention in the kidneys, with subsequent oedema.

However, several experimental and clinical observations
Nephrotic syndrome made over the years do not support this hypothesis.

EXPERIMENTAL AND CLINICAL OBSERVATIONS

Albuminuria AGAINST THE UNDERFILL HYPOTHESIS 1,2 (Table 1)

Patients and laboratory rats with low serum

albumin levels do not develop oedema or sodium
retention
Hypoalbuminaemia
Joles et al3 measured the plasma and interstitial oncotic
pressure of Nagase rats, which are mutant rats
characterised by analbuminaemia. The researchers found
Reduction in plasma oncotic pressure
no signs of sodium retention in those animals.
Furthermore, Lecomte et al 4 carried out observations on
patients with congenital analbuminaemia and found that
Translocation of fluid from the intravascular space most had no oedema. Many other published series of
to the interstitial space patients with congenital analbuminaemia do not report the
appearance of oedema as the main symptom.5 Steyl et al 6
studied 50 patients hospitalised in a general medical ward
in South Africa and noted that 24 patients had a serum
Decrease in effective arterial blood volume
albumin level lower than 3.5g/dl, mostly associated with
chronic inflammation (tuberculosis). Of these 24 patients,

! Renin-angiotensin-aldosterone system
! Sympathetic nervous system
! Arginine-vasopressin
" Atrial natriuretic peptide Table 1. Arguments against the underfill hypothesis
o f oedema f ormation in nephrotic syndrome

Sodium and water retention by the kidney 1. Patients and laboratory rats with low serum albumin levels
do not develop oedema or sodium retention.
2. Natriuresis in the recovery phase of nephrotic syndrome
Oedema begins when proteinuria disappears but before serum
albumin returns to normal levels.
3. The absolute decrease in plasma oncotic pressure does not

Figure 1. Classic or underfill hypothesis of oedema formation affect the volume of the intravascular space in nephrotic
in nephrotic syndrome. syndrome.
4. Plasma and blood volumes are normal or increased in
nephrotic syndrome.
5. Intravascular space expansion with albumin does not

movement of fluid from the intravascular space to the increase natriuresis in patients with nephrotic syndrome.
interstitial space, causing a decrease in effective arterial 6. The activation of the renin-angiotensin-aldosterone system
blood volume and consequently, relative hypovolaemia. is not involved in the development of oedema in nephrotic
This would then result in activation of the renin-
angiotensin-aldosterone and sympathetic nervous syndrome.
systems, increased antidiuretic hormone release and 7. Bilateral adrenalectomy does not prevent sodium retention
inhibition of atrial natriuretic peptide release. Activation in nephrotic syndrome in laboratory rats.
of these systems would cause sodium and water

Nefrologia 2011;31(2):148-54 149

 H. Rondon-Berrios. O edema in nephrotic syndrome
sh or t re v ie w s

only six had oedema. These six patients with oedema had The activation of the renin-angiotensin-aldosterone
an alternative diagnosis that clearly explained the presence system is not involved in the development of
of oedema (cor pulmonale). During the study, they found oedema in nephrotic syndrome
some patients with serum albumin levels below 1.5g/dl,
but none of them had oedema. Brown et al12, administered captopril to a group of NS
patients and observed no change in sodium excretion despite
suppressing serum aldosterone concentrations. In another
Natriuresis in the recovery phase of nephrotic study, Usberti et al13 reported similar findings when using
syndrome begins when proteinuria disappears but spironolactone.
before serum albumin returns to normal levels7

The absolute decrease in plasma oncotic pressure Adrenalectomy does not prevent sodium retention
does not affect the volume of the intravascular and the development of ascites in nephrotic
space in nephrotic syndrome syndrome in laboratory rats

Studies performed on dogs suggest that the absolute De Seigneux et al studied a group of rats from which they
decrease in plasma oncotic pressure would not affect had removed both adrenal glands. The rats were
plasma or blood volume. 8 Patients with NS caused by administered dexamethasone to prevent adrenal failure.14 The
glomerulonephritis were studied by measuring their researchers induced NS in the rats by administering
plasma and interstitial oncotic pressure: 12 patients in the puromycin. The rats developed oedema and sodium retention
active phase, 3 in complete remission and 3 in partial despite having been adrenalectomised. These findings
remission. 9 The researchers found that plasma and suggest that aldosterone does not play a major role in sodium
interstitial oncotic pressure were decreased in the active retention that is characteristic of NS.
phase of NS but slowly returned to normal values during
remission. During this time, the oncotic pressure gradient
between plasma and interstitium was constant. 9 These ALTERNATIVE HYPOTHESIS OR OVERFILL
studies show that it is the change in the oncotic pressure HYPOTHESIS OF OEDEMA FORMATION IN
gradient between plasma and interstitium and not just the NEPHROTIC SYNDROME
absolute decrease in plasma oncotic pressure that causes
the movement of fluid from the intravascular to the Contrary to the classic hypothesis, the alternative hypothesis
interstitial space. (also called the overfill hypothesis) postulates that sodium
retention in many NS patients is a primary renal
phenomenon and may be caused by an intrinsic renal defect
Plasma and blood volumes are normal or increased in sodium excretion, which in turn causes an expansion in
in nephrotic syndrome plasma volume (hence the term overfill). Although the
molecular mechanism of sodium retention in the kidneys has
Geers et al10 measured plasma volumes in 88 patients with not been clearly explained, there are a number of studies on
NS and in 51 controls. Plasma volume was measured by this topic, which we describe below.
administration of radioactive albumin I. 131 Blood volume
was calculated based on plasma volume and haematocrit.
The plasma and blood volume of NS patients was found Molecular mechanisms of sodium retention
to be high in 14%, normal in 84% and low in only 2% of in nephrotic syndrome
cases.
The first observations supporting the overfill hypothesis
were made by Chandra15 and Ichikawa.16 Most of our
Intravascular space expansion with albumin does understanding of the molecular mechanisms of sodium
not increase natriuresis in patients with nephrotic retention in NS has come from the use of animal models that
syndrome induced NS by puromycin aminonucleoside (PAN). When
PAN is administered to rats, it causes massive proteinuria
The effect of an intravenous infusion of hyperoncotic and sodium retention. The renal histopathology induced by
albumin (75g) was observed in patients with NS. 11 After PAN resembles minimal change disease.17-19 Using the
the infusion, blood volume increased up to 120% of technique of selective unilateral perfusion through the left
baseline. Plasma renin activity and serum aldosterone renal artery with PAN first described by Bricker in dogs20
concentration decreased to the point of being and later by Hoyer in rats,21 Chandra15 and Ichikawa16 showed
suppressed. Urinary sodium excretion did not change that proteinuria and sodium retention were confined to the
significantly. kidney perfused with PAN. The unilateral NS model allows

150 Nefrologia 2011;31(2):148-54

H. Rondon-Berrios. O edema in nephrotic syndrome
sh or t re v ie w s

the study of a proteinuric kidney and a control kidney in the pump. Deschenes et al24 found that the activity of this pump
same animal. It must be emphasised that the sodium was increased in rats treated with PAN when compared to
retention by the kidney perfused with PAN occurred without control rats. These authors also observed that the increase in
a reduction in plasma protein concentration, suggesting that pump activity was confined to the cortical collecting
the sodium retention observed in NS was due to an intrinsic tubule.24 However, many subsequent studies have shown
renal defect in sodium excretion rather than due to extrinsic that, in rats treated with PAN, the activity of this pump and
or systemic factors such as hypoalbuminaemia. other sodium transporters (such as NHE3) is decreased when
compared to control rats.25

The cortical collecting tubule is the reabsorption

point for sodium in nephrotic syndrome The role of ENaC in sodium retention in nephrotic
syndrome
Ichikawa16 also performed micropuncture studies of
superficial nephron tubular segments in the unilateral NS Another sodium transporter that has been reported to be
model in rats, and showed that the amount of sodium at the strongly involved in sodium retention in NS is the epithelial
end of the distal convoluted tubule is the same in the sodium channel or amiloride-sensitive sodium channel
proteinuric kidney as in the normal kidney. The final urine of (ENaC). ENaC is composed of three subunits: , , and .
the nephrotic kidney, however, contained three times less The first studies conducted on the role of ENaC in sodium
sodium than the urine from the normal kidney, suggesting retention in NS showed that there was no increase in protein
that stimulation of sodium reabsorption in the NS occurs in expression (nor mRNA) of any of the three subunits of
the cortical collecting tubule. ENaC in rats treated with PAN when compared to control
rats.26 However, subsequent studies have shown an increase
in protein expression of the three subunits of ENaC,14,25 as
The role of NHE3 in sodium retention in the NS well as an increase in the movement of these subunits from
the cytosol to the apical plasma membrane.
Despite the findings of Ichikawa et al, other studies have
postulated that sodium retention in NS may occur in other ENaC is regulated by several factors, one of which is the
nephron segments. Sixty-six percent of sodium filtered by enzyme 11--hydroxysteroid dehydrogenase type 2
the glomerulus is reabsorbed in the proximal tubule by the (11HSD2). Mineralocorticoid receptor activation causes an
action of the Na-H cotransporter (NHE3). It would be increase in ENaC activity by increasing expression of the
reasonable then to assume that this segment would, at least gene that encodes the ENaC subunit and a decrease in its
in part, contribute to the sodium retention observed in NS. intracellular recycling system mediated by the ubiquitin
Besse-Eschmann et al22 found that NHE3 activity ligase Nedd4-2.27 Cortisol has the same affinity as
(normalised to the amount of protein) was increased by 88% aldosterone to the mineralocorticoid receptor. However,
in rats treated with PAN, compared to control rats. NHE3 is aldosterone acts as the sole agonist of this receptor even
present at two locations of the proximal tubular brush though the concentration of cortisol in plasma is 100 times
border, forming oligomers: 1) in the intervillous space, the concentration of aldosterone. The 11HSD2 enzyme
where it is associated with the megalin receptor (a protein usually protects the mineralocorticoid receptor from cortisol
responsible for the reabsorption of albumin and other activation by locally transforming it into cortisone, which is
substances filtered by the glomerulus), representing the inactive on this receptor. Nevertheless, in pathological states
inactive form of NHE3, and 2) in the microvillous space, such as in the syndrome of apparent mineralocorticoid
where it is free and represents the active form of the excess, the activity of the 11HSD2 enzyme is reduced,
transporter.23 The researchers also found that in rats treated allowing the cortisol to activate the mineralocorticoid
with PAN there was NHE3 movement from the intervillous receptor and cause sodium retention.28 A study by Kim et al29
space to the microvillus space.22 They suggested that showed that the activity of the 11HSD2 enzyme is reduced
albumin filtered by the NSs defective glomerular barrier in rats with NS caused by mercuric chloride-induced
could dissociate NHE3 from megalin and increase membranous nephropathy when compared to control rats,
movement of NHE3 to the microvilli so that it might which may explain the sodium retention in these animals.
perform its sodium retention function from there.22 However, other studies have not confirmed these findings.14,30

Another important factor in the regulation of ENaC is the

The role of the Na+ /K+-ATPase pump in sodium group of serine proteases. These are a group of proteolytic
retention in nephrotic syndrome enzymes that cleave the and ENaC subunits in specific
sites and thereby increase sodium conductance through the
Another sodium transporter that has been reported to be channel.31,32 Under experimental conditions, sodium
involved in sodium retention in NS is the Na+/K+-ATPase conductance is low in ENaC that has not been exposed to

Nefrologia 2011;31(2):148-54 151

 H. Rondon-Berrios. O edema in nephrotic syndrome
sh or t re v ie w s

proteolysis by serine proteases. The first step in ENaC previously described results with urine from NS patients. To
activation by serine proteases occurs in the Golgi complex, summarise, the plasminogen present in plasma is probably
where a protease called furin cleaves the subunit at the filtered through NSs own defective glomerular barrier and is
R205 and R231 sites (thus releasing an inhibitory peptide of then converted into plasmin by the action of urokinase
26 amino acids) and the subunit at the R143 site.33 If this present in the collecting tubule. Plasmin would then activate
ENaC conductance were measured under experimental ENaC, resulting in sodium retention with the subsequent
conditions, it would be intermediate. After this enzymatic appearance of oedema (Figure 2).
process, the channel is assembled in the apical plasma
membrane. For ENaC to be completely active and have high
sodium conductance, it must be activated by a second protease The use of amiloride to treat nephrotic oedema
(such as prostasin, neutrophil elastase or pancreatic elastase).34
Treatment of oedema in NS is traditionally based on a low
The first observations on ENaC activation by serine sodium diet (2.3g of sodium a day or 6g of sodium chloride
proteases in proteinuric states were made by Kastner et al.35 a day) and the use of loop diuretics. Amiloride is a
Passero et al36 found that ENaC currents increased when potassium-sparing diuretic and its use has traditionally been
ENaC was exposed to plasmin, suggesting that plasmin acts restricted to the prevention of hypopotassaemia associated
as a second protease and is capable of activating ENaC. with the use of loop diuretics. However, according to the
Passero36 also discovered that plasmin activates ENaC by findings described above, the use of amiloride may play an
cleaving the subunit at the K194 site. important role in the treatment of oedema in NS. In our
clinical experience, the use of amiloride enhances diuresis
Perhaps the most convincing evidence to date about the role caused by loop diuretics. This has been reproduced
of serine proteases in ENaC activation in NS is the recently experimentally41 and has also been reported in other clinical
published report by Svenningsen et al.37 They found that studies.42 We usually start treatment of nephrotic oedema
urine in nephrotic rats treated with PAN increased the ENaC with a 1mg dose of bumetanide orally twice a day and a 5mg
currents and that amiloride abolished them. Svenningsen et dose of amiloride orally once a day. Amiloride should not be
al investigated why the urine of these nephrotic rats used in isolation but rather in combination with loop
activated ENaC and found that the ENaC currents were diuretics, given that although the collecting tubule plays a
abolished when ENaC was exposed to aprotinin, a known key role in sodium retention in NS, in absolute terms it only
inhibitor of serine proteases. Another important observation contributes 4% of total filtered sodium reabsorption.
was that the urine of nephrotic rats did not increase ENaC
currents when subjected to heat. When serine protease
activity in this urine was measured, it was found to be high.
All these findings suggest that the urine of nephrotic rats
Plasminogen
contains a serine protease capable of activating ENaC.37
Several previous studies performed on NS patients have
documented the presence of plasminogen in the urine of Defective
these patients.38,39 After several purification steps and mass glomerular
spectrometry (MALDI-TOF), Svenningsen et al found that barrier
plasminogen and/or plasmin were the serine proteases
responsible for ENaC activation in the urine of nephrotic
rats. The urine of nephrotic rats contained both substances, Principal cell
Collecting
but the plasma from these animals only contained tubule
plasminogen, suggesting that plasmin was formed in the
urine in situ and was not filtered out of the plasma.37 Plasmin Plasminogen
is known to come from the activation of plasminogen uPA Principal cell
through the enzymatic action of urokinase, which is Plasmin
inactive
normally present in the collecting tubule.40 Svenningsen et ENaC
al37 observed that the cortical collecting tubule cells of
nephrotic rats had urokinase activity. They also observed
that while the combination of plasminogen and urokinase Plasmin Active
ENaC
increased ENaC currents in oocytes, plasminogen and Na+
urokinase were incapable of doing so in isolation.37 Another
important finding was that amiloride not only blocks ENaC
but also blocks the urokinase enzyme responsible for uPa: urokinase
converting plasminogen into plasmin.37 Significantly,
Svenningsen et al37 were able to reproduce all of the Figure 2. Plasmin in the cortical collecting duct activates ENaC.

152 Nefrologia 2011;31(2):148-54

H. Rondon-Berrios. O edema in nephrotic syndrome
sh or t re v ie w s

KEY CONCEPTS

1. In a large number of NS patients, the 5. The defective glomerular barrier in NS allo ws the
pathophysiology of oedema is not related to the passage of many proteins, among them
presence of hypoalbuminaemia, decreased plasminogen.
intravascular space volume or secondary 6. Urokinase, an enzyme naturally present in the
hyperaldosteronism. cortical collecting tubule epithelium, is responsible
2. NS oedema is caused by an intrinsic renal defect in for converting plasminogen into plasmin.
sodium excretion. 7. Plasmin, formed in situ in the cortical collecting
3. Sodium retention in NS occurs in the cortical tubule, activates ENaC causing sodium retention
collecting tubule. and oedema.
4. ENaC, one of the sodium transporters present in 8. A miloride enhances diuresis caused by loop
the cortical collecting tubule, is involved in sodium diuretics in NS.
retention in NS.

REFERENCES 14. De Seigneux S, Kim SW, Hemmingsen SC, et al. Increased expres-
sion but not targeting of ENaC in adrenalectomized rats with PAN-
1. Deschenes G, Guigonis V, Doucet A. Molecular mechanism of ede- induced nephrotic syndrome. Am J Physiol Renal Physiol
ma formation in nephrotic syndrome. Arch Pediatr 2004;11:1084- 2006;291:F208-17.
94. 15. Chandra M, Hoyer JR, Lewy JE. Renal function in rats with unilate-
2. Doucet A, Favre G, Deschenes G. Molecular mechanism of edema ral proteinuria produced by renal perfusion with aminonucleoside.
formation in nephrotic syndrome: therapeutic implications. Pediatr Pediatr Res 1981;15:340-4.
Nephrol 2007;22:1983-90. 16. Ichikawa I, Rennke HG, Hoyer JR, et al. Role for intrarenal mecha-
3. Joles JA, Willekes-Koolschijn N, Braam B, et al. Colloid osmotic pres- nisms in the impaired salt excretion of experimental nephrotic
sure in young analbuminemic rats. Am J Physiol 1989;257:F23-28. syndrome. J Clin Invest 1983;71:91-103.
4. Lecomte J, Juchmes J. So-called absence of edema in analbumine- 17. Caulfield JP, Reid JJ, Farquhar M G. Alterations of the glomerular epi-
mia. Rev Med Liege 1978;33:766-70. thelium in acute aminonucleoside nephrosis. Evidence for formation
5. Koot BG, Houwen R, Pot DJ, et al. Congenital analbuminaemia: bio- of occluding junctions and epithelial cell detachment. Lab Invest
chemical and clinical implications. A case report and literature re- 1976;34:43-59.
view. Eur J Pediatr 2004;163:664-70. 18. Fiegelson EB, Drake JW, Recant L. Experimental aminonucleoside
6. Steyl C, Van Zyl-Smit R. Mechanisms of oedema formation: the mi- nephrosis in rats. J Lab Clin Med 1957;50:437-46.
nor role of hypoalbuminaemia. S Afr Med J 2009;99:57-9. 19. Ryan GB, Karnovsky MJ. An ultrastructural study of the mechanisms
7. Oliver WJ. Physiologic Responses Associated with Steroid-Induced of proteinuria in aminonucleoside nephrosis. Kidney Int 1975;8:219-
Diuresis in the Nephrotic Syndrome. J Lab Clin Med 1963;62:449- 32.
64. 20. Bricker NS, Stokes JM, Lubowitz H, et al. Experimentally induced
8. Manning RD, Jr., Guyton A C. Effects of hypoproteinemia on fluid permanent unilateral renal disease in dogs. J Lab Clin Med
volumes and arterial pressure. Am J Physiol 1983;245:H284-93. 1958;52:571-9.
9. Koomans HA, Kortlandt W, Geers AB, et al. Lowered protein con- 21. Hoyer JR, Mauer SM, Michael AF. Unilateral renal disease in the rat.
tent of tissue fluid in patients with the nephrotic syndrome: obser- I. Clinical, morphologic, and glomerular mesangial functional featu-
vations during disease and recovery. Nephron 1985;40:391-5. res of the experimental model produced by renal perfusion with
10. Geers AB, Koomans HA, Boer P, et al. Plasma and blood volumes in aminonucleoside. J Lab Clin Med 1975;85:756-68.
patients with the nephrotic syndrome. Nephron 1984;38:170-3. 22. Besse-Eschmann V, Klisic J, Nief V, et al. Regulation of the proximal
11. Koomans HA, Geers AB, vd Meiracker AH, et al. Effects of plasma tubular sodium/proton exchanger NHE3 in rats with puromycin ami-
volume expansion on renal salt handling in patients with the neph- nonucleoside (PAN)-induced nephrotic syndrome. J Am Soc Nephrol
rotic syndrome. Am J Nephrol 1984;4:227-34. 2002;13:2199-206.
12. Brown EA, Markandu ND, Sagnella G A, et al. Lack of effect of cap- 23. Biemesderfer D, DeGray B, Aronson PS. Active (9.6 s) and inactive
topril on the sodium retention of the nephrotic syndrome. Nephron (21 s) oligomers of NHE3 in microdomains of the renal brush bor-
1984;37:43-8. der. J Biol Chem 2001;276:10161-7.
13. Usberti M, Gazzotti RM. Hyporeninemic hypoaldosteronism in pa- 24. Deschenes G, Gonin S, Zolty E, et al. Increased synthesis and avp
tients with nephrotic syndrome. Am J Nephrol 1998;18:251-5. unresponsiveness of Na,K-ATPase in collecting duct from nephrotic

Nefrologia 2011;31(2):148-54 153

 H. Rondon-Berrios. O edema in nephrotic syndrome
sh or t re v ie w s

rats. J Am Soc Nephrol 2001;12:2241-52. 34. Passero CJ, Hughey RP, Kleyman TR. New role for plasmin in sodium
25. Kim SW, Wang W, Nielsen J, et al. Increased expression and apical homeostasis. Curr Opin Nephrol Hypertens;19:13-9.
targeting of renal ENaC subunits in puromycin aminonucleoside-in- 35. Kastner C, Pohl M, Sendeski M, et al. Effects of receptor-mediated
duced nephrotic syndrome in rats. Am J Physiol Renal Physiol endocytosis and tubular protein composition on volume retention
2004;286:F922-35. in experimental glomerulonephritis. Am J Physiol Renal Physiol
26. Audige A, Yu ZR, Frey BM, et al. Epithelial sodium channel (ENaC) 2009;296:F902-11.
subunit mRNA and protein expression in rats with puromycin ami- 36. Passero CJ, Mueller G M, Rondon-Berrios H, et al. Plasmin activates
nonucleoside-induced nephrotic syndrome. Clin Sci (Lond) epithelial Na channels by cleaving the gamma subunit. J Biol Chem
2003;104:389-95. 2008;283:36586-91.
27. Loffing J, Korbmacher C. Regulated sodium transport in the renal 37. Svenningsen P, Bistrup C, Friis UG, et al. Plasmin in nephrotic urine
connecting tubule (CNT) via the epithelial sodium channel (ENaC). activates the epithelial sodium channel. J Am Soc Nephrol
Pflugers Arch 2009;458:111-35. 2009;20:299-310.
28. Hammer F, Stewart PM. Cortisol metabolism in hypertension. Best 38. Lau SO, Tkachuck JY, Hasegawa DK, et al. Plasminogen and antith-
Pract Res Clin Endocrinol Metab 2006;20:337-53. rombin III deficiencies in the childhood nephrotic syndrome associa-
29. Kim SW, De Seigneux S, Sassen M C, et al. Increased apical targe- ted with plasminogenuria and antithrombinuria. J Pediatr
ting of renal ENaC subunits and decreased expression of 11be- 1980;96:390-2.
taHSD2 in HgCl2-induced nephrotic syndrome in rats. Am J Physiol 39. Vaziri ND, Gonzales EC, Shayestehfar B, et al. Plasma levels and uri-
Renal Physiol 2006;290:F674-87. nary excretion of fibrinolytic and protease inhibitory proteins in
30. Bistrup C, Thiesson HC, Jensen BL, et al. Reduced activity of 11beta- nephrotic syndrome. J Lab Clin Med 1994;124:118-24.
hydroxysteroid dehydrogenase type 2 is not responsible for sodium 40. Piedagnel R, Tiger Y, Lelongt B, et al. Urokinase (u-PA) is produced
retention in nephrotic rats. Acta Physiol Scand 2005;184:161-9. by collecting duct principal cells and is post-transcriptionally regula-
31. Hamm LL, Feng Z, Hering-Smith KS. Regulation of sodium transport ted by SV40 large-T, arginine vasopressin, and epidermal growth
by ENaC in the kidney. Curr Opin Nephrol Hypertens; 19:98-105. factor. J Cell Physiol 2006;206:394-401.
32. Kleyman TR, Carattino MD, Hughey RP. ENaC at the cutting edge: 41. Deschenes G, Wittner M, Stefano A, et al. Collecting duct is a site
regulation of epithelial sodium channels by proteases. J Biol Chem of sodium retention in PAN nephrosis: a rationale for amiloride the-
2009;284:20447-51. rapy. J Am Soc Nephrol 2001;12:598-601.
33. Hughey RP, Bruns JB, Kinlough CL, et al. Epithelial sodium channels 42. Guigonis V, Nathanson S, Doucet A, Deschenes G. Amiloride poten-
are activated by furin-dependent proteolysis. J Biol Chem tiates edema removal by furosemide in nephrotic children. J Am Soc
2004;279:18111-4. Nephrol 2001;12: 135A.

Sent for reiew: 8 Nov. 2010 | Accepted el: 16 Nov. 2010

154 Nefrologia 2011;31(2):148-54