α-Melanocyte Stimulating Hormone (MSH) decreases cyclosporine A induced apoptosis in cultured human proximal tubular cells

Abstract

The pathogenesis of chronic cyclosporine A (CsA) nephrotoxicity has not been elucidated, but apoptosis is thought to play an important role in CsA induced tubular atrophy. Recently Fas-Fas ligand system mediated apoptosis has been frequently reported in many epithelial cells as well as in T lymphocytes. We investigated the ability of CsA to induce apoptosis in cultured human proximal tubular epithelial cells and also the effect of alpha-MSH on them. Fas, Fas ligand, and an intracellular adaptor protein, Fas-associating protein with death domain (FADD) expression, and poly-ADP ribose polymerase (PARP) cleavage were also studied. CsA induced apoptosis in cultured tubular epithelial cells demonstrated by increased number of TUNEL positive cells and it was accompanied by a significant increase in Fas mRNA and Fas ligand protein expressions. FADD and the cleavage product of PARP also increased, indicating the activation of caspase. In alpha-MSH co-treated cells, apoptosis markedly decreased with downregulation of Fas, Fas ligand and FADD expressions and also the cleavage product of PARP. In conclusion, these data suggest that tubular cell apoptosis mediated by Fas system may play a role in tubular atrophy in chronic CsA nephrotoxicity and pretreatment of alpha-MSH may have a some inhibitory effect on CsA induced tubular cell apoptosis.

The Effect of ??-Melanocyte???Stimulating Hormone on Renal Tubular Cell Apoptosis and Tubulointerstitial Fibrosis in Cyclosporine A Nephrotoxicity

“…Since Shihab et al (18) reported induction of the apoptotic gene, Fas, FasL, and p53, in CsA nephrotoxicity, many investigators have reported the mechanism of apoptosis on CsA nephrotoxicity (11,13,14). In this study, we have demonstrated that CsA induced apoptosis in rat renal tubular cells by TUNEL stain.…”

“…Most organs undergoing fibrosis will show a paucity of cells, suggesting that apoptosis may be playing an active role in the later stages of fibrosis (10). Our previous studies showed that tubular cell apoptosis can serve as a part of chronic CsA nephrotoxicity and Fas/FasL systems, and their downstream signaling molecules, FADD and PARP cleavages, can mediate apoptotic cell death in cultured renal tubular cells on CsA stimulation, and these findings were alleviated by ␣-melanocyte-stimulating hormone (MSH) treatment (11). ␣-MSH is a proopiomelanocortin derivative and is an endogenous cytokine that suppresses inflammation in various animal models by means of its inhibitory action on proinflammatory cytokines and chemoattractant cytokines (12)(13)(14)(15).…”

Migration of leukocytes across an endothelium-epithelium bilayer as a model of renal interstitial inflammation

“…This suggests ␣-MSH may affect both the PMN and the endothelial cells. Although an anti-inflammatory and cytoprotective effect of ␣-MSH have been reported also for tubular epithelial cells (10,14),transmigration across HK-2 monolayers was not influenced by ␣-MSH (data not shown), making their importance in ␣-MSH-inhibited migration unlikely. Our data show sequential migration of PMN across endothelial and renal tubular epithelial cells.…”

“…␣-Melanocyte-stimulating hormone (␣-MSH), a potent anti-inflammatory peptide, has been shown to be effective in animal models of local and systemic inflammatory disorders, including sepsis syndrome, and inflammatory bowel disease, and acute renal failure (14,17,22). The effects of ␣-MSH are mediated by melanocortin receptors found on macrophages, polymorphonuclear neutrophils (PMN), and renal tubular cells and acts by inhibiting maladaptive activation of genes that cause inflammatory and cytotoxic injury (5,10). However, the effect of ␣-MSH on PMN migration is not known.…”

The Role of Endotoxin in the Setting of Cardiorenal Syndrome Type 5

“…Acute tubular apoptosis was demonstrated by different techniques in patients with septic AKI, whereas almost no apoptosis was detected in patients with nonseptic AKI. Moreover, in an experimental model of cultured human proximal tubular cells, Jo et al [43] demonstrated that endotoxin, TNF-α and other pro-inflammatory cytokines induced apoptosis of renal proximal tubular cells.…”