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Loss of NOS1 expression in high-grade renal cell carcinoma associated with a shift of NO signalling
K Renaudin1, M G Denis, G Karam
1Pathology Department, CHU Hôtel Dieu, 30 Boulevard Jean Monnet, 44093 Nantes Cedex 1, France.
Abstract:
In normal human kidney, NOS1 and soluble guanylate cyclase (sGC) are expressed in tubular epithelial cells, suggesting a physiological autocrine NO signalling pathway. Therefore, we investigated both NOS1 and sGC expressions in benign and malignant renal tumours. In addition, we examined the pattern of protein tyrosine nitration in normal and tumour tissue. NOS1 expression and activity were found to be downregulated, correlating with the tumour grade, as shown by immunohistochemistry, quantitative RT-PCR analysis, and histochemical detection of the NADPH-diaphorase activity of nitric oxide synthases (NOS). These results show that the autocrine NO signalling pathway is maintained in benign tumours and lost in malignant tumours. In contrast, sGC expression was maintained in renal tumours whatever the tumour type, a finding showing that tumour cells remain sensitive to the bioregulatory role of exogeneous NO(*). Finally, the staining pattern of protein tyrosine nitration, assessed by immunohistochemistry, parallelled that of NOS1 expression in normal renal parenchyma and benign tumours, supporting the concept that protein nitration was accounted for by NOS1 activity. In contrast, in malignant tumours, protein tyrosine nitration was accounted for by the production of reactive nitrogen oxide species by the inflammatory infiltrate. Altogether, these findings argue for a pattern of NO signalling similar in normal kidney and benign renal tumours, whereas it is completely different in malignant renal tumours.
Insights
Nitric oxide (NO) signaling via NOS1 is maintained in benign kidney tumors but lost in malignant ones. Soluble guanylate cyclase (sGC) remains expressed, indicating potential sensitivity to external NO.
Area of Science:
- Nephrology
- Molecular Biology
- Cancer Research
Background:
- The nitric oxide (NO) signaling pathway, involving NOS1 and soluble guanylate cyclase (sGC), is physiologically active in normal human kidney tubular epithelial cells.
- This pathway suggests an autocrine mechanism for NO regulation within the kidney.
Purpose of the Study:
- To investigate the expression and activity of NOS1 and sGC in benign and malignant renal tumors.
- To analyze the pattern of protein tyrosine nitration in normal and tumorous kidney tissues.
Main Methods:
- Immunohistochemistry to assess NOS1 and sGC expression.
- Quantitative RT-PCR for gene expression analysis.
- Histochemical detection of NADPH-diaphorase activity for NOS activity.
- Immunohistochemistry to evaluate protein tyrosine nitration patterns.
Main Results:
- NOS1 expression and activity were downregulated in renal tumors, correlating with tumor grade.
- The autocrine NO signaling pathway was preserved in benign tumors but lost in malignant tumors.
- sGC expression remained consistent across all renal tumor types, suggesting retained sensitivity to exogenous NO.
- Protein tyrosine nitration patterns mirrored NOS1 expression in normal and benign tissues, but in malignant tumors, it was linked to inflammatory infiltrate-derived reactive nitrogen species.
Conclusions:
- The NO signaling pathway in kidney tumors differs significantly between benign and malignant types.
- Benign renal tumors maintain a NO signaling pattern similar to normal kidney tissue.
- Malignant renal tumors exhibit a distinct NO signaling profile, with altered NOS1 activity and protein nitration sources.
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