Molecular mechanism of edema formation in nephrotic syndrome: therapeutic implications

Alain Doucet, Guillaume Favre, Georges Deschênes, Alain Doucet, Guillaume Favre, Georges Deschênes

Abstract

Sodium retention and edema are common features of nephrotic syndrome that are classically attributed to hypovolemia and activation of the renin-angiotensin-aldosterone system. However, numbers of clinical and experimental findings argue against this underfill theory. In this review we analyze data from the literature in both nephrotic patients and experimental models of nephrotic syndrome that converge to demonstrate that sodium retention is not related to the renin-angiotensin-aldosterone status and that fluid leakage from capillary to the interstitium does not result from an imbalance of Starling forces, but from changes of the intrinsic properties of the capillary endothelial filtration barrier. We also discuss how most recent findings on the cellular and molecular mechanisms of sodium retention has allowed the development of an efficient treatment of edema in nephrotic patients.

Figures

Fig. 1
Fig. 1
Cellular mechanism of sodium reabsorption in principal cells of collecting ducts from normal rats and nephrotic rats. Sodium reabsorption in principal cells proceeds along a two-step mechanism that includes active extrusion of intracellular sodium ions by the basolateral Na,K-ATPase and passive apical entry of sodium via the amiloride-sensitive epithelial sodium channel (ENaC). In CCDs from normal rats (top panels), most ENaCs are sequestered in the intracellular compartment of principal cells (left panel), and basolateral expression of Na,K-ATPase in collecting ducts (asterisk) principal cells is very weak, in comparison with that in thick ascending limbs (T) and even proximal tubules (P) (right panel). Accordingly, the rate of sodium reabsorption is very low. In CCDs from PAN nephrotic rats (bottom panels), ENaC is expressed at the apical border of principal cells (left panel), and expression of basolateral Na,K-ATPase is drastically increased in collecting ducts (asterisk). Polarized increases in expression of ENaC and Na,K-ATPase in principal cells account for increased sodium reabsorption in CCDs. In both normal and nephrotic rats expression of Na,K-ATPase is undetectable in the glomerulus (G); in CCDs, unlabeled cells for both ENaC and Na,K-ATPase are intercalated cells (redrawn from [13, 14])
Fig. 2
Fig. 2
Profile of sodium excretion in PAN nephrotic rats. Daily urinary sodium excretion, expressed as a function of urinary creatinine excretion, following administration of puromycin aminonucleoside (150 mg/kg body wt, intravenously) in normal rats (dotted lines) or genetically modified or pharmacologically treated rats (solid lines). Arrows or grey boxes show the time of treatment. Brattleboro rats genetically lack vasopressin secretion. JB1, an inhibitor of IGF-1 receptors, was continuously administered via subcutaneous mini-pumps at a dose of 12 μg/100 g body wt per day, starting on day 3. The antagonist of AT1 receptor, irbesartan, was administered per os at a dose of 2 mg/100g body wt per day. Etanercept, a chimeric antibody directed against TNF receptor, was administered twice (days −1 and 2) at a dose of 0.2 mg/100g body wt. The inhibitor of nitric oxide synthase, L-NAME, was administered twice daily by gavage (0.5 mg/100 g body wt per 12 h) throughout the study. The antagonist of PPARγ, SR202, was given per os at a dose of 20 mg/100 g body wt. All controls were treated in parallel with the vehicle. Values are means ± SE from 4–5 rats

References

    1. Deschenes G, Doucet A. Collecting duct (Na+/K+)-ATPase activity is correlated with urinary sodium excretion in rat nephrotic syndromes. J Am Soc Nephrol. 2000;11:604–615.
    1. Pedraza-Chaverri J, Cruz C, Ibarra-Rubio ME, Chavez MT, Calleja C, Tapia E, del Carmen Uribe M, Romero L, Pena JC. Pathophysiology of experimental nephrotic syndrome induced by puromycin aminonucleoside in rats. I. The role of proteinuria, hypoproteinemia, and renin–angiotensin–aldosterone system on sodium retention. Rev Invest Clin. 1990;42:29–38.
    1. Ichikawa I, Rennke HG, Hoyer JR, Badr KF, Schor N, Troy JL, Lechene CP, Brenner BM. Role for intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome. J Clin Invest. 1983;71:91–103.
    1. Feraille E, Doucet A. Sodium–potassium–adenosinetriphosphatase-dependent sodium transport in the kidney: hormonal control. Physiol Rev. 2001;81:345–418.
    1. Deschenes G, Wittner M, Stefano A, Jounier S, Doucet A. Collecting duct is a site of sodium retention in PAN nephrosis: a rationale for amiloride therapy. J Am Soc Nephrol. 2001;12:598–601.
    1. Perico N, Delaini F, Lupini C, Benigni A, Galbusera M, Boccardo P, Remuzzi G. Blunted excretory response to atrial natriuretic peptide in experimental nephrosis. Kidney Int. 1989;36:57–64.
    1. Rabelink AJ, Koomans HA, Gaillard CA, Dorhout Mees EJ. Renal response to atrial natriuretic peptide in nephrotic syndrome. Nephrol Dial Transplant. 1987;2:510–514.
    1. Valentin JP, Ying WZ, Couser WG, Humphreys MH. Extrarenal resistance to atrial natriuretic peptide in rats with experimental nephrotic syndrome. Am J Physiol. 1998;274:F556–F563.
    1. Feraille E, Vogt B, Rousselot M, Barlet-Bas C, Cheval L, Doucet A, Favre H. Mechanism of enhanced Na-K-ATPase activity in cortical collecting duct from rats with nephrotic syndrome. J Clin Invest. 1993;91:1295–1300.
    1. Vogt B, Favre H. Na+,K(+)-ATPase activity and hormones in single nephron segments from nephrotic rats. Clin Sci (Lond) 1991;80:599–604.
    1. de Seigneux S, Kim SW, Hemmingsen SC, Frokiaer J, Nielsen S. Increased expression but not targeting of ENaC in adrenalectomized rats with PAN-induced nephrotic syndrome. Am J Physiol Renal Physiol. 2006;291:F208–F217.
    1. Kim SW, de Seigneux S, Sassen MC, Lee J, Kim J, Knepper MA, Frokiaer J, Nielsen S. Increased apical targeting of renal ENaC subunits and decreased expression of 11betaHSD2 in HgCl2-induced nephrotic syndrome in rats. Am J Physiol Renal Physiol. 2006;290:F674–F687.
    1. Lourdel S, Loffing J, Favre G, Paulais M, Nissant A, Fakitsas P, Creminon C, Feraille E, Verrey F, Teulon J, Doucet A, Deschenes G. Hyperaldosteronemia and activation of the epithelial sodium channel are not required for sodium retention in puromycin-induced nephrosis. J Am Soc Nephrol. 2005;16:3642–3650.
    1. Deschenes G, Gonin S, Zolty E, Cheval L, Rousselot M, Martin PY, Verbavatz JM, Feraille E, Doucet A. Increased synthesis and avp unresponsiveness of Na,K-ATPase in collecting duct from nephrotic rats. J Am Soc Nephrol. 2001;12:2241–2252.
    1. Epstein AA. Concerning the causation of edema in chronic parenchymatous nephritis; method for its alleviation. Am J Med. 1952;13:556–561.
    1. Lecomte J, Juchmes J. So-called absence of edema in analbuminemia. Rev Med Liege. 1978;33:766–770.
    1. Oliver WJ. Physiologic responses associated with steroid-induced diuresis in the nephrotic syndrome. J Lab Clin Med. 1963;62:449–464.
    1. Vande Walle J, Donckerwolcke R, Boer P, van Isselt HW, Koomans HA, Joles JA. Blood volume, colloid osmotic pressure and F-cell ratio in children with the nephrotic syndrome. Kidney Int. 1996;49:1471–1477.
    1. Tsau YK, Chen CH, Tsai WS, Sheu JN. Complications of nephrotic syndrome in children. J Formos Med Assoc. 1991;90:555–559.
    1. Geers AB, Koomans HA, Boer P, Dorhout Mees EJ. Plasma and blood volumes in patients with the nephrotic syndrome. Nephron. 1984;38:170–173.
    1. Deschenes G, Guigonis V, Doucet A. Molecular mechanism of edema formation in nephrotic syndrome. Arch Pediatr. 2004;11:1084–1094.
    1. Brown EA, Markandu ND, Sagnella GA, Jones BE, MacGregor GA. Lack of effect of captopril on the sodium retention of the nephrotic syndrome. Nephron. 1984;37:43–48.
    1. Usberti M, Gazzotti RM. Hyporeninemic hypoaldosteronism in patients with nephrotic syndrome. Am J Nephrol. 1998;18:251–255.
    1. Coutry N, Farman N, Bonvalet JP, Blot-Chabaud M. Synergistic action of vasopressin and aldosterone on basolateral Na(+)-K(+)-ATPase in the cortical collecting duct. J Membr Biol. 1995;145:99–106.
    1. Vinciguerra M, Mordasini D, Vandewalle A, Feraille E. Hormonal and nonhormonal mechanisms of regulation of the Na,K-pump in collecting duct principal cells. Semin Nephrol. 2005;25:312–321.
    1. Peti-Peterdi J, Warnock DG, Bell PD. Angiotensin II directly stimulates ENaC activity in the cortical collecting duct via AT(1) receptors. J Am Soc Nephrol. 2002;13:1131–1135.
    1. Jabri N, Schalch DS, Schwartz SL, Fischer JS, Kipnes MS, Radnik BJ, Turman NJ, Marcsisin VS, Guler HP. Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients. Diabetes. 1994;43:369–374.
    1. Gonzalez-Rodriguez E, Gaeggeler HP, Rossier BC. IGF-1 vs insulin: respective roles in modulating sodium transport via the PI-3 kinase/Sgk1 pathway in a cortical collecting duct cell line. Kidney Int. 2007;71:116–125.
    1. Vinciguerra M, Hasler U, Mordasini D, Roussel M, Capovilla M, Ogier-Denis E, Vandewalle A, Martin PY, Feraille E. Cytokines and sodium induce protein kinase A-dependent cell-surface Na,K-ATPase recruitment via dissociation of NF-kappaB/IkappaB/protein kinase A catalytic subunit complex in collecting duct principal cells. J Am Soc Nephrol. 2005;16:2576–2585.
    1. DiPetrillo K, Coutermarsh B, Gesek FA. Urinary tumor necrosis factor contributes to sodium retention and renal hypertrophy during diabetes. Am J Physiol Renal Physiol. 2003;284:F113–F121.
    1. Guan Y, Hao C, Cha DR, Rao R, Lu W, Kohan DE, Magnuson MA, Redha R, Zhang Y, Breyer MD. Thiazolidinediones expand body fluid volume through PPAR gamma stimulation of EnaC-mediated renal salt absorption. Nat Med. 2005;11:861–8661.
    1. Zhang H, Zhang A, Kohan DE, Nelson RD, Gonzalez FJ, Yang T. Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention. Proc Natl Acad Sci U S A. 2005;102:9406–9411.
    1. Martin PY, Ohara M, Gines P, Xu DL, St John J, Niederberger M, Schrier RW. Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites. J Clin Invest. 1998;101:235–242.
    1. Lewis DM, Tooke JE, Beaman M, Gamble J, Shore AC. Peripheral microvascular parameters in the nephrotic syndrome. Kidney Int. 1998;54:1261–1266.
    1. Joles JA, Willekes-Koolschijn N, Braam B, Kortlandt W, Koomans HA, Dorhout Mees EJ. Colloid osmotic pressure in young analbuminemic rats. Am J Physiol. 1989;257:F23–F28.
    1. Joles JA, Koomans HA, Kortlandt W, Boer P, Dorhout Mees EJ. Hypoproteinemia and recovery from edema in dogs. Am J Physiol. 1988;254:F887–F894.
    1. Koomans HA, Kortlandt W, Geers AB, Dorhout Mees EJ. Lowered protein content of tissue fluid in patients with the nephrotic syndrome: observations during disease and recovery. Nephron. 1985;40:391–395.
    1. Fauchald P, Noddeland H, Norseth J. An evaluation of ultrafiltration as treatment of diuretic-resistant oedema in nephrotic syndrome. Acta Med Scand. 1985;217:127–131.
    1. Wiig H, Reed RK. Interstitial compliance and transcapillary Starling pressures in cat skin and skeletal muscle. Am J Physiol. 1985;248:H666–H673.
    1. Noddeland H, Riisnes SM, Fadnes HO. Interstitial fluid colloid osmotic and hydrostatic pressures in subcutaneous tissue of patients with nephrotic syndrome. Scand J Clin Lab Invest. 1982;42:139–146.
    1. Clarke H, Soler AP, Mullin JM. Protein kinase C activation leads to dephosphorylation of occludin and tight junction permeability increase in LLC-PK1 epithelial cell sheets. J Cell Sci. 2000;113:3187–3196.
    1. Yuan SY, Ustinova EE, Wu MH, Tinsley JH, Xu W, Korompai FL, Taulman AC. Protein kinase C activation contributes to microvascular barrier dysfunction in the heart at early stages of diabetes. Circ Res. 2000;87:412–417.
    1. He P, Curry FE. Albumin modulation of capillary permeability: role of endothelial cell [Ca2+]I. Am J Physiol. 1993;265:H74–H82.
    1. Suranyi MG, Guasch A, Hall BM, Myers BD. Elevated levels of tumor necrosis factor-alpha in the nephrotic syndrome in humans. Am J Kidney Dis. 1993;21:251–259.
    1. Ferro T, Neumann P, Gertzberg N, Clements R, Johnson A. Protein kinase C-alpha mediates endothelial barrier dysfunction induced by TNF-alpha. Am J Physiol Lung Cell Mol Physiol. 2000;278:L1107–L1117.
    1. Rostoker G, Behar A, Lagrue G. Vascular hyperpermeability in nephrotic edema. Nephron. 2000;85:194–200.
    1. Avasthi PS. Effects of aminonucleoside on rat blood–peritoneal barrier permeability. J Lab Clin Med. 1979;94:295–302.
    1. Prandota J. Pharmacokinetics of furosemide urinary elimination by nephrotic children. Pediatr Res. 1983;17:141–147.
    1. Agarwal R, Gorski JC, Sundblad K, Brater DC. Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome. J Am Soc Nephrol. 2000;11:1100–1105.
    1. Kirchner KA, Voelker JR, Brater DC. Binding inhibitors restore furosemide potency in tubule fluid containing albumin. Kidney Int. 1991;40:418–424.
    1. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K. Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol Cell. 1998;1:575–582.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe