Glucocorticoid therapy: minimizing side effects

Longui, Carlos Alberto

doi:10.2223/jped.1713

Cited by 54 publications

(48 citation statements)

References 11 publications

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“…Although most children and adults presenting with NS respond to glucocorticoids, the clinical outcome is often not satisfactory, given the high frequency of relapses, the high proportion of steroid-resistant patients, and the significant side effects of this treatment (28,36). Alternative medications such as cyclophosphamide, mycophenolate, and calcineurin inhibitors are available; however, they each have their own shortcomings in terms of efficacy and side effects.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Pengal

Guess

Agrawal

et al. 2011

American Journal of Physiology-Renal Physiology

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While mitogen-activated protein kinase (MAPK) activation has been implicated in the pathogenesis of various glomerular diseases, including nephrotic syndrome (NS), its specific role in podocyte injury is not known. We hypothesized that MK-2, a downstream substrate of p38 MAPK, mediates the adverse effects of this pathway and that inhibition of MK-2 would protect podocytes from NS-related injury. Using cultured podocytes, we analyzed 1) the roles of MK-2 and p38 MAPK in puromycin aminonucleoside (PAN)-induced podocyte injury; 2) the ability of specific MK-2 and p38 MAPK inhibitors to protect podocytes against injury; 3) the role of serum albumin, known to induce podocyte injury, in activating p38 MAPK/MK-2 signaling; and 4) the role of p38 MAPK/MK-2 signaling in the expression of Cox-2, an enzyme associated with podocyte injury. Treatment with protein kinase inhibitors specific for both MK-2 (C23, a pyrrolopyridine-type compound) or p38 MAPK (SB203580) reduced PAN-induced podocyte injury and actin cytoskeletal disruption. Both inhibitors reduced baseline podocyte p38 MAPK/MK-2 signaling, as measured by the degree of phosphorylation of HSPB1, a downstream substrate of MK-2, but exhibited disparate effects on upstream signaling. Serum albumin activated p38 MAPK/MK-2 signaling and induced Cox-2 expression, and these responses were blocked by both inhibitors. Given the critical importance of podocyte injury to both NS and other progressive glomerular diseases, these data suggest an important role for p38 MAPK/MK-2 signaling in podocyte injury and identify MK-2 inhibition as a promising potential therapeutic strategy to protect podocytes in various glomerular diseases.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Pengal

Guess

Agrawal

et al. 2011

American Journal of Physiology-Renal Physiology

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“…As far back as 1950 it was noted on the base of clinical observations that it needs at least 5-7 days of corticosteroids use before appearance of ulcer symptoms (Sandweiss, 1954). One of the principles for minimizing undesirable side effects of glucocorticoid therapy is "keep treatment as short as possible, since treatment lasting 5 to 7 days shows fewer side effect" (Longui, 2007). It is more often glucocorticoid-induced ulcer symptoms appeared after much more long hormonal treatment.…”

Section: Discussionmentioning

confidence: 99%

Dual action of glucocorticoid hormones on the gastric mucosa: how the gastroprotective action can be transformed to the ulcerogenic one

et al. 2009

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Glucocorticoid hormones have dual action on the stomach: gastroprotective and ulcerogenic one. The present study was designed to investigate how physiological gastroprotective action of glucocorticoids can be transformed to pathological ulcerogenic effect. Dose- and time-dependent effects of single injection of dexamethasone on indomethacin-induced gastric erosions, corticosterone and blood glucose levels, somatic parameters were investigated in rats. Dexamethasone at the doses of 0.1, 1, 10 mg/kg decreased the gastric erosion area dose dependently in the case of its injection 1 h before indomethacin administration. Gastroprotective action of dexamethasone (at a dose of 1 mg/kg) was also observed in the case of its injection 6 and 12 h before indomethacin. However, the further increase in the time interval caused transformation of gastroprotective action of dexamethasone to ulcerogenic one. Accordingly to the data obtained short-term maintenance of blood glucose level provides the gastroprotective action of dexamethasone, while dexamethasone-induced long-lasting maintenance of blood glucose level accompanied with the signs of catabolic effects may be responsible at least partly for its ulcerogenic effect.

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“…The most commonly used treatment for NS is oral glucocorticoids (GC), which effectively induce remission in the majority of children. However, GC have severe side effects, and ϳ20% of patients develop or present with resistance to GC therapy (9,12). Despite their frequent use, neither the target cells nor the mechanism of action of GC in inducing remission in NS have been clearly identified.…”

mentioning

confidence: 99%

Dose- and time-dependent glucocorticoid receptor signaling in podocytes

Guess

Agrawal

Wei

et al. 2010

American Journal of Physiology-Renal Physiology

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Glucocorticoids (GC) are the primary therapy for idiopathic nephrotic syndrome (NS). Recent evidence has identified glomerular podocytes as a potential site of GC action in this disease. The objectives of this study were to determine the presence of key components of the glucocorticoid receptor (GR) complex and the functionality of this signaling pathway in podocytes and to explore potential opportunities for manipulation of GC responsiveness. Here, we show that cultured murine podocytes express key components of the GR complex, including the GR, heat shock protein 90, and the immunophilins FKBP51 and FKBP52. The functionality of GR-mediated signaling was verified by measuring several GC (dexamethasone)-induced responses, including 1) increases in mRNA and protein levels of selected GC-regulated genes (FKBP51, phenol sulfotransferase 1, αB-crystallin); 2) downregulation of the GR protein; 3) increased phosphorylation of the GR; and 4) translocation of the GR into the nuclear fraction. Dexamethasone-induced phosphorylation and downregulation of GR protein were also demonstrated in isolated rat glomeruli. Podocyte gene expression in response to dexamethasone was regulated at both the transcriptional and posttranscriptional levels, the latter also including protein degradation. Short-term, high-dose GC treatment resulted in similar changes in gene expression and GR phosphorylation to that of long-term, low-dose GC treatment, thus providing a molecular rationale for the known efficacy of pulse GC therapy in NS. Induction of FKBP51 and downregulation of the GR represent negative feedback mechanisms that can potentially be exploited to improve clinical GC efficacy. Collectively, these findings demonstrate the presence of key molecular components of the GR signaling pathway and its functionality in podocytes and identify novel opportunities for improving clinical GC efficacy in the treatment of NS.

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Glucocorticoid therapy: minimizing side effects

Cited by 54 publications

References 11 publications

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Dual action of glucocorticoid hormones on the gastric mucosa: how the gastroprotective action can be transformed to the ulcerogenic one

Dose- and time-dependent glucocorticoid receptor signaling in podocytes

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