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

Mühl, Heiko; Sandau, Katrin; Brüne, Bernhard; Briner, Verena; Pfeilschifter, Josef

doi:10.1016/s0014-2999(96)00701-7

Cited by 91 publications

(63 citation statements)

References 43 publications

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“…Increased production of NO may exert a cytotoxic effect either directly or, alternatively, by reacting with superoxide to form the much more toxic peroxynitrite anion, especially when it is massively produced by macrophages (47). Additional tissue injury may result from NO-induced cell apoptosis (48) and from enhanced prostanoid synthesis consequent to cyclooxygenase activation (49). It should also be noted that iNOS can produce superoxide anions rather than NO under conditions of absolute or relative L-arginine deficiency (50,51) and could therefore promote NO-independent renal injury.…”

Section: Discussionmentioning

confidence: 99%

Evidence for the Existence of Two Distinct Functions for the Inducible NO Synthase in the Rat Kidney

Fujihara¹,

Mattar²,

Vieira³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. The functional role of the NO synthase (NOS) isoforms in the normal or diseased kidney is uncertain. This study examined the renal expression of the endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) isoforms by both immunohistochemistry and Western blot analyses in shamoperated rats (S) and in rats subjected to 5/6 nephrectomy (Nx). Primary antibodies from two different sources were used to detect iNOS. Additional S and Nx rats were chronically treated with aminoguanidine (AG), a selective iNOS inhibitor. All three isoforms were clearly expressed in S kidney. Their renal abundance, evaluated by Western blot analysis, fell in Nx rats. With the use of anti-iNOS antibodies from two distinct sources, the immunohistochemical analysis showed the presence of what appeared to be two distinct iNOS fractions: a "tubular" fraction, present in S and with decreased intensity in Nx; and an "interstitial" fraction, observed only in inflamed areas of Nx rats. AG treatment greatly attenuated renal injury in Nx rats by a direct antiinflammatory effect, likely related to iNOS inhibition, rather than to amelioration of renal hemodynamics or to reduced protein glycation. These observations suggest that: (1) the functional role of the renal iNOS isoform may vary dramatically under different physiologic conditions; (2) caution should be taken in the interpretation of immunohistochemical iNOS data, because antibodies from different sources may detect different iNOS fractions; and (3) AG treatment may become useful in the treatment of human progressive nephropathies, even those not associated with diabetes or aging.

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Section: Discussionmentioning

confidence: 99%

Evidence for the Existence of Two Distinct Functions for the Inducible NO Synthase in the Rat Kidney

Fujihara¹,

Mattar²,

Vieira³

et al. 2002

Journal of the American Society of Nephrology

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“…M freshly isolated from CSF-1-deficient, obstructed kidneys had a reduced expression of the cell surface activation markers CD69 (an early activation marker whose expression is rapidly induced upon activation) (22) and CD23 (a low affinity receptor for IgE expressed on M and shown to mediate activation and proinflammatory response, including release of NO (23-25) and MHC class II markers (Ia k,b )). NO and TNF-␣ induce apoptosis (26,27). In CSF-1-deficient kidneys, iNOS, the enzyme that produces NO, and TNF-␣ expression is reduced compared with that in WT kidneys (Fig.…”

Section: Csf-1-deficient Obstructed Kidney M Are Less Activated Thanmentioning

confidence: 93%

Reduced Macrophage Recruitment, Proliferation, and Activation in Colony-Stimulating Factor-1-Deficient Mice Results in Decreased Tubular Apoptosis During Renal Inflammation

Lenda

Kikawada

Stanley

et al. 2003

The Journal of Immunology

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Kidney tubular epithelial cell (TEC) death may be dependent on the number and activation state of macrophages (Mφ) during inflammation. Our prior studies indicate that activated Mφ release soluble mediators that incite TEC death, and reducing intrarenal Mφ during kidney disease diminishes TEC apoptosis. CSF-1 is required for Mφ proliferation and survival. We hypothesized that in the absence of CSF-1, Mφ-mediated TEC apoptosis would be prevented during renal inflammation. To test this hypothesis, we evaluated renal inflammation during unilateral ureter obstruction in CSF-1-deficient (Csf1op/Csf1op) mice. We detected fewer Mφ and T cells and less apoptotic TEC in the obstructed kidneys of Csf1op/Csf1op mice compared with wild-type (WT) mice. The decrease in intrarenal Mφ resulted from diminished recruitment and proliferation, not enhanced apoptosis. CSF-1 enhanced Mφ activation. There were far fewer activated (CD69, CD23, Ia, surface expression) Mφ in obstructed CSF-1-deficient compared with WT obstructed kidneys. Similarly, bone marrow Mφ preincubated with anti-CSF-1 receptor Ab or anti-CSF-1 neutralizing Ab were resistant to LPS- and IFN-γ-induced activation. We detected fewer apoptotic-inducing molecules (reactive oxygen species, TNF-α, inducible NO synthase) in 1) Mφ propagated from obstructed Csf1op/Csf1op compared with WT kidneys, and 2) WT bone marrow Mφ blocked with anti-CSF-1 receptor or anti-CSF-1 Ab compared with the isotype control. Furthermore, blocking CSF-1 or the CSF-1 receptor induced less TEC apoptosis than the isotype control. We suggest that during renal inflammation, CSF-1 mediates Mφ recruitment, proliferation, activation, and, in turn, TEC apoptosis.

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“…However, the capacity to limit the growth of MC populations was clearly enhanced by concomitant suppression of MC mitosis. Indeed, exogenous NO donors have been reported to induce DNA fragmentation and inhibit mitosis in MC (42,43). It is known that when MC are treated with the NO donor, S-nitroso-glutathione, the nuclear protein p53, whose effects on the cell cycle are well recognized, is induced (42).…”

Section: Figurementioning

confidence: 99%

“…Indeed, exogenous NO donors have been reported to induce DNA fragmentation and inhibit mitosis in MC (42,43). It is known that when MC are treated with the NO donor, S-nitroso-glutathione, the nuclear protein p53, whose effects on the cell cycle are well recognized, is induced (42). Furthermore, exogenous NO donors activate caspase 8, the most upstream member of the caspase pathway, by cleavage, in lymphoid cell lines (44).…”

Section: Figurementioning

confidence: 99%

Activated Macrophages Direct Apoptosis and Suppress Mitosis of Mesangial Cells

Duffield

Erwig

Xiao

et al. 2000

The Journal of Immunology

109

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During inflammation in the glomerulus, the complement of resident myofibroblast-like mesangial cells is regulated by mitosis and apoptosis, but the cellular mechanisms controlling the size of mesangial cell populations have remained obscure. Prompted by studies of development, we sought evidence that macrophages regulate mesangial cell number. Rat bone marrow-derived macrophages primed with IFN-γ then further activated in coculture with LPS or TNF-α elicited a 10-fold induction of rat mesangial cell apoptosis and complete suppression of mitosis, effects inhibitable by the NO synthase inhibitors l-monomethyl arginine and l-N6-(1-iminoethyl) lysine dihydrochloride. Complete dependence upon macrophage-derived NO was observed in comparable experiments employing activated bone marrow macrophages from wild-type and NO synthase 2−/− mice. Nevertheless, when mesangial cells were primed with IFN-γ plus TNF-α, increased induction by activated macrophages of mesangial apoptosis exhibited a NO-independent element. The use of gld/gld macrophages excluded a role for Fas ligand in this residual kill, despite increased expression of Fas and increased susceptibility to soluble Fas ligand exhibited by cytokine-primed mesangial cells. Finally, activated macrophages isolated from the glomeruli of rats with nephrotoxic nephritis also induced apoptosis and suppressed mitosis in mesangial cells by an l-monomethyl arginine-inhibitable mechanism. These data demonstrate that activated macrophages, via the release of NO and other mediators, regulate mesangial cell populations in vitro and may therefore control the mesangial cell complement at inflamed sites.

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

Cited by 91 publications

References 43 publications

Evidence for the Existence of Two Distinct Functions for the Inducible NO Synthase in the Rat Kidney

Evidence for the Existence of Two Distinct Functions for the Inducible NO Synthase in the Rat Kidney

Reduced Macrophage Recruitment, Proliferation, and Activation in Colony-Stimulating Factor-1-Deficient Mice Results in Decreased Tubular Apoptosis During Renal Inflammation

Activated Macrophages Direct Apoptosis and Suppress Mitosis of Mesangial Cells

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