Abstract
Nephrotic syndrome is a common disorder in adults and children whose etiology is largely unknown. Glucocorticoids remain the mainstay of therapy in most cases, though their mechanism of action remains poorly understood. Emerging evidence suggests that immunomodulatory therapies used in nephrotic syndrome directly target the podocytes. To study how steroids directly affect the podocytes in the treatment of proteinuria, we created a mouse model with podocyte-specific deletion of the glucocorticoid receptor. The podocyte-specific glucocorticoid receptor (GR) knockout mice had similar renal function and protein excretion compared to wild type. However, after glomerular injury induced by either LPS or nephrotoxic serum, the podocyte GR knockout mice demonstrated worsened proteinuria compared to wild type. Ultrastructural examination of podocytes confirmed more robust foot process effacement in the knockout animals. Expression of several key slit diaphragm protein was down regulated in pGR KO mice. Primary podocytes isolated from wild type and podocyte GR knockout mice showed similar actin stress fiber staining patterns in unstimulated conditions. Yet, when exposed to LPS, GR knockout podocytes demonstrated fewer stress fibers and impaired migration compared to wild type podocytes. We conclude that the podocyte glucocorticoid receptor is important for limiting proteinuria in settings of podocyte injury.
Highlights
Nephrotic syndrome is one of the most common kidney diseases in both children and adults
No perinatal mortality was observed in Podocyte GR KO (pGR KO) mice indicating that podocyte glucocorticoid receptor (GR) is not required for postnatal renal development. Podocyte-specific GR (pGR) KO mice gained weight normally and demonstrated normal activity and behavior until at least 1 year of age
We found a strong trend toward worsened foot process effacement, though not reaching statistical significance, in the pGR KO mice treated with both protamine sulfate and with heparin rescue compared to the control mice under similar conditions
Summary
Nephrotic syndrome is one of the most common kidney diseases in both children and adults. The decision to treat with glucocorticoids remains largely empiric, since the mechanism of action whereby they induce nephrotic syndrome remission is not well understood and their target cells in this setting have not been clearly identified. Some of the earliest studies suggested a serum factor that decreased T cell function in patients with nephrotic syndrome[6, 7]. B cells have recently been shown to play a role in the pathophysiology of this condition through the therapeutic effect, in some patients, of rituximab, a B-cell inhibitor[10]. Studies in animal models have clearly shown a role for complement in the development of nephrotic syndrome[11, 12] and nearly two dozen cytokines[13], as well as the transcription factor NF-κB14, have been implicated in the pathogenesis of this condition. The mechanistic link between administration of steroids, acting through cell-specific GR, and suppression of inflammation is central to this process
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