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Nitric oxide donors induce apoptosis in glomerular mesangial cells, epithelial cells and endothelial cells.

Abstract：

:Renal mesangial cells exposed to inflammatory cytokines produce high concentrations of nitric oxide (NO) which may exert cytotoxic actions. We report here that glomerular mesangial cells, endothelial cells and epithelial cells in culture are themselves targets for NO and undergo apoptotic cell death upon exposure to high concentrations of NO. NO generated from different NO-releasing compounds as well as NO-saturated solution induce apoptosis in all three cell types as demonstrated by internucleosomal DNA fragmentation, an enrichment of cytosolic DNA/histone complexes, an increasing number of cellular 3'-OH-fragmented DNA ends and typical nuclear chromatin condensation. Induction of apoptosis was found to be dependent on protein synthesis and is preceded by expression of the tumour suppressor gene product p53 in mesangial cells. Induction of inducible NO synthase in mesangial cells by interleukin-1 beta leads to excessive formation of NO by the cells as measured by nitrite production. However, there was no evidence for apoptotic changes in mesangial cells triggered by endogenously produced NO. Co-cultures of glomerular endothelial or epithelial cells with interleukin-1 beta-activated mesangial cells expressing inducible NO synthase do not show apoptotic alterations in endothelial or epithelial cells. Moreover, preincubation of mesangial cells with interleukin-1 beta protects the cells from apoptosis induced by subsequent addition of exogenous NO thus suggesting that interleukin-1 beta not only triggers the expression of inducible NO synthase and massive NO formation but simultaneously stimulates a protecting principle in the cells. In summary, these results suggest that exogenous NO can induce apoptosis in all three types of intrinsic glomerular cells. However, whether endogenously produced NO can fulfil this function critically depends on a balance between a yet to be defined protective mechanism and inducible NO synthase expression in mesangial cells in response to interleukin-1 beta and eventually other inflammatory cytokines.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Mühl H,Sandau K,Brüne B,Briner VA,Pfeilschifter J

doi

10.1016/s0014-2999(96)00701-7

subject

Has Abstract

pub_date

1996-12-12 00:00:00

pages

137-49

issue

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(96)00701-7

journal_volume

317

pub_type

杂志文章

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Nitric oxide donors induce apoptosis in glomerular mesangial cells, epithelial cells and endothelial cells.