NDT Advance Access originally published online on April 10, 2008
Nephrology Dialysis Transplantation 2008 23(9):3037-3038; doi:10.1093/ndt/gfn178
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Reply
E-mail: bernd.hohenstein{at}uk-erlangen.deSir,
In response to the comment by Komers and Anderson we would like to add some important thoughts to the discussion on the relevance of the present study [1]. Several studies demonstrating the relevance of many cofactors and modifications of the eNOS enzyme have been published but a discrepancy between patient related and experimental data may occur [2]. Clearly, one major concern with respect to the arguments forwarded by Komers and Anderson is the comparability of experimental models and human disease. Furthermore, many studies, and especially the ones cited by Komers and Anderson, do not demonstrate any histological data from the experiments in diabetic kidneys. Others demonstrate data from a follow-up of 4–6 weeks of experimental diabetes [2], which, at best, leads to mild histological changes. Even late time points (20 weeks or more) of experimental models never reflect the severe histological injury found in human kidneys with diabetic nephropathy. Therefore, to date little is known about the up- or downregulation of eNOS activity in human kidneys with diabetic nephropathy that we have investigated in our study [1]. We acknowledge, however, that studies in biopsies with early diabetic nephropathy hardly exist, and most lack thorough assessment of functional data.
Hollenberg et al. demonstrated that in patients with hyperfiltration and high local RAS, treatment with irbesartan led to unexpectedly enhanced renal plasma flow, indirectly suggesting enhanced NO action during this early phase of diabetic nephropathy [3], but no histological examination has been carried out at the same time.
In summary, we agree that our study cannot provide sufficient information on eNOS-related NO generation. We suggest that eNOS does not generate enough NO to completely reverse endothelial dysfunction and prevent ongoing injury to the diabetic kidney. However, the increase in eNOS expression points to a compensatory mechanism to counteract the increased oxidative stress in diabetes.
Thus, as stated in our manuscript, further functional studies of NO activity in humans will be necessary to determine the activity of the NO system in human diabetic nephropathy in more detail.
Conflict of interest statement. None declared.
Medizinische Klinik 4-Nephrologie und Hypertensiologie, Universität Erlangen-Nürnberg, Loschgestrasse 8, D-91054 Erlangen, Germany
References
- Hohenstein B, Hugo CP, Hausknecht B, et al. Analysis of NO-synthase expression and clinical risk factors in human diabetic nephropathy. Nephrol Dial Transplant (2008) 4:1346–1354.
- Komers R, Anderson S. Paradoxes of nitric oxide in the diabetic kidney. Am J Physiol Renal Physiol (2003) 284:F1121–F1137.
[Abstract/Free Full Text] - Price DA, Porter LE, Gordon M, et al. The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol (1999) 10:2382–2391.
[Abstract/Free Full Text]
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