—  RENAL PATHOLOGY SOCIETY   —

Novel Insight Into the Pathogenesis of Nephrotic Syndrome


Peter Mundel
Albert Einstein College of Medicine
New York, NY


Podocytes are important for glomerular biology and pathology. Podocytes are terminally differentiated cells that line the outer aspect of the glomerular basement membrane. Podocytes therefore forms the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Podocytes are highly differentiated cells with limited capability to undergo cell division in the adult. Their function is largely based on complex cell architecture loss of podocytes is a hallmark of progressive renal disease [1] . Podocytes play a key role in the development and progression of most glomerular diseases including Minimal change disease, Congenital Nephrotic Syndrome, Familial and Secondary FSGS, Denys-Drash Syndrome, Frasier Syndrome, Diabetic nephropathy, Chronic glomerulonephritis, Collapsing idiopathic glomerulopathy and HIV-asociated glomerulopathy [1] . The podocyte slit diaphragm is dynamic site of glomerular permselectivity. The SD represents is made up of rod-like units connected in the center to a linear bar forming a zipper like appearance and is organized in lipid rafts. The recent discovery of several SD proteins and their mutation analysis including nephrin, the nephrin homologue(s) neph1(-3), CD2AP, podocin, and the protocadherin FAT shed light on the pathogenesis of proteinuria . These findings emphasized the critical role of the SD for the function of the glomerular filtration barrier. In addition to the SD, it has become clear that the podocyte actin cytoskeleton plays a central integrative role in the regulation of glomerular filtration and for the progression to ESRD [2] .

Podocyte foot processes (FP) are defined by three membrane domains - the apical membrane domain, the SD protein complex and the basal membrane domain or sole plate. All three compartments are linked to the FP actin cytoskeleton. The FP actin cytoskeleton is highly dynamic as shown in the acute PS/heparin model of reversible FP effacement. Interference with one of the three domains changes the actin cytoskeleton from coordinated parallel bundles into a dense network with FP effacement and obliteration of filtration slits. Proteins regulating or stabilizing F-actin like α-actinin-4 or synaptopodin are therefore of critical importance for sustained function of glomerular filtration [2] . Podocytes of a3 integirn deficient (a3-/-)mice are unable to maintain normal podocyte structure, including the elaboration of mature foot processes along the GBM [3] . To identify genes critically involved in the development of FP effacement and proteinuria, we performed a genomic screen comparing wild type and a 3-/- podocytes. With this approach we uncovered a unanticipated novel role for B7-1 in podocytes as inducible modifier of glomerular permselectivity [4] . B7-1 in podocytes was found in genetic, drug-induced, immune-mediated and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome [4] . The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. LPS signaling through TLR-4 re-organized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins [4] . In vivo, LPS rapidly upregulated B7-1 in podocytes of wild type and SCID mice leading to nephrotic range proteinuria. Mice lacking B7-1 were protected from LPS-induced nephrotic syndrome. Take together these data established a causal link between podocyte B7-1 expression and urinary protein loss that is independent of lymphocyte infiltration or activation [4] . It has not escaped out attention that LPS induced nephrotic syndrome shares several key features of human MCD in that the FP effacement and proteinuria are transient and present without signs of glomerular inflammation. The upregulation of B7-1 in podocytes suits well to provide a unifying molecular explanation for the pathogenesis of proteinuria in nephrotic syndrome. However, it is difficult to believe that the sole (and harmful) function of podocyte B7-1 should be to disassemble the glomerular filter. Hence, it is intriguing to speculate that transient B7-1 dependent proteinuria may be a physiological response that is desirable under certain conditions, e.g. in patients with gram-negative infection. The disruption of the glomerular filter by TLR-induced B7-1 may help the innate immune system in clearing the circulation from harmful agents by dumping them into the urine the urine. In this scenario, the transient urinary protein loss would be the price that we pay for the rapid decay of the harmful agent. Consistent with this idea, the development of transient proteinuria has been found during the course of gram negative sepsis [5] . Moreover, a prospective study showed that in postoperative septic patients microalbuminuria is an early indicator of increased glomerular permeability, but not in non-septic patients [6] . Clearly, this is highly speculative and future studies will be required to explore this hypothesis in detail. In MCD, the onset of nephrotic syndrome is often preceded by an infection or allergic reaction [7] . Some children present with fever and bacteremia. In a number of these patients, the peritoneal cavity is the site of the infection and Streptococcus pneumoniae, Staphylococcus aureus and Escherichia coli are commonly isolated [7] . A urinary tract infection is occasionally present and a history of upper respiratory tract infection immediately preceding the first clinical signs of nephrotic syndrome may exist and stimulate the activation of podocyte danger signaling pathways, thereby leading to B7-1 induced nephrotic syndrome. This raises the intriguing possibility that prolonged nephrotic syndrome in MCD may result from the persistence of a normally beneficial response caused by genetic defects in the B7-1 pathway or by the persistence of other unphysiological activators of podocyte B71. The sustained B7-1 activation in podocytes, in turn, may result in the continuation or recurrence of nephrotic syndrome in this setting.

The activation of the innate immune system by LPS [4] (and potentially other pathogen associated particles) leads to the upregulation of podocyte B7-1. In the light of these results is tempting to speculate that podocyte B7-1 may not only act to reorganize the slit diaphragm but participate in the activation of circulating T-cells. Under normal conditions T-cells are unable to enter the glomerulus but in advanced stages of nephrotic syndrome, it may be facilitated for T-cells to enter Bowman's space and directly interact with podocytes. A podocyte-T-cell interaction may result in stimulation and activation of T-cells. In inflammatory glomerulonephritis, T-cells can be found in the glomerulus in Bowman's space and B7-1 as well as B7-2 regulate crescentic glomerulonephritis [8] . Therefore, podocyte B7-1 may also modulate T-cell-mediated cytotoxicity in immune and nonimmune kidney diseases with proteinuria. The expression of B7-1 by podocytes in glomerulonephritic situations may serve to recruit T-cells to sites of GBM damage and breakdown, and promote further inflammation [9] . In summary, taking advantage of our increasing molecular knowledge about the role of podocytes in the pathogenesis of Nephrotic Syndrome, it should be possible to development of "podocyte-protective" drugs. Such podocyte-specific drugs may promote SD protein expression/localization/function, promote recovery from foot process effacement and Prevent detachment/loss of podocytes.

References

  1. Somlo, S., and Mundel, P. 2000. Getting a foothold in nephrotic syndrome. Nat Genet 24:333-335.

  2. Mundel, P., and Shankland, S.J. 2002. Podocyte biology and response to injury. J Am Soc Nephrol 13:3005-3015.

  3. Kreidberg, J.A., Donovan, M.J., Goldstein, S.L., Rennke, H., Shepherd, K., Jones, R.C., and Jaenisch, R. 1996. Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development 122:3537-3547.

  4. Reiser, J., Von Gersdorff, G., Loos, M., Oh, J., Asanuma, K., Giardino, L., Rastaldi, M.P., Calvaresi, N., Watanabe, H., Schwarz, K., et al. 2004. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 113:1390-1397.

  5. Pacquement, H., Sinnassamy, P., Quintana, E., Thomas, C., Bensman, A., and Zucker, J.M. 1989. [Nephrotic syndrome and B leukemia]. Arch Fr Pediatr 46:741-742.

  6. De Gaudio, A.R., Adembri, C., Grechi, S., and Novelli, G.P. 2000. Microalbuminuria as an early index of impairment of glomerular permeability in postoperative septic patients. Intensive Care Med 26:1364-1368.

  7. Eddy, A.A., and Schnaper, H.W. 1998. The nephrotic syndrome: from the simple to the complex. Semin Nephrol 18:304-316.

  8. Kinoshita, K., Tesch, G., Schwarting, A., Maron, R., Sharpe, A.H., and Kelley, V.R. 2000. Costimulation by B7-1 and B7-2 is required for autoimmune disease in MRL-faslpr mice. J Immunol 164:6046-6056.

  9. Reiser, J., and Mundel, P. 2004. Danger signaling by glomerular podocytes defines a novel function of inducible b7-1 in the pathogenesis of nephrotic syndrome. J Am Soc Nephrol 15:2246-2248.