NDT Advance Access originally published online on July 2, 2008
Nephrology Dialysis Transplantation 2008 23(9):3037; doi:10.1093/ndt/gfn174
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Glomerular endothelial NOS (eNOS) expression in type 2 diabetic patients with nephropathy
E-mail: rako{at}medicon.cz, komersr{at}ohsu.eduSir,
Bioavailability of nitric oxide (NO) in the diabetic kidney has been a subject of numerous studies in various experimental settings. Paradoxically, both enhanced NO production and endothelial dysfunction, as a consequence of impaired NO generation by endothelial NO synthase (eNOS), have been implicated in the pathophysiology of diabetic nephropathy [1].
In the recent issue of NDT, Hohenstein and co-workers [2] report increases in expression and different patterns of distribution of eNOS in glomeruli from type 2 diabetic patients with nephropathy. The eNOS expression was higher in patients with more severe proteinuria and correlated with the severity of vascular complications. The authors assume that enhanced eNOS protein expression indicates parallel increases in NO production, and state that their findings strengthen the view that NO activity is stimulated in diabetic nephropathy. Moreover, they suggest that the kidney circulation is endowed by a specific ability to upregulate eNOS in the face of decreasing NO bioavailability in the systemic circulation.
The authors should be commended for addressing this issue in the clinical context. However, the data should be interpreted with caution, reflecting current knowledge about eNOS pathobiochemistry in diabetes. To function as an NO-producing enzyme, eNOS requires a battery of cofactors, posttranslational modifications such as phosphorylation and dimerization, protein–protein interactions and subcellular targeting [3]. We have recently explored renal cortical protein expression of eNOS with respect to these determinants of its enzymatic function, in streptozotocin-diabetic (DM) rats and control animals [4]. Despite similar whole cell eNOS expression in all groups, eNOS monomer and dimer in membrane fractions were reduced in DM compared to controls; the opposite trend was apparent in the cytosol. Stimulatory phosphorylation of eNOS on Serine 1177 was also reduced in DM. Some of these findings are consistent with eNOS ‘uncoupling’ in the diabetic kidney, i.e. a phenomenon characterized by diversion of electron transfer within the eNOS molecule from L-arginine oxidation, resulting in reduction of molecular oxygen to form superoxide instead of NO. Indeed, parallel studies by others [5] proved eNOS uncoupling as the major source of local superoxide production in the diabetic kidney. Together, these studies indicate that mere determination of total eNOS protein, without consideration of posttranslational modifications, does not provide sufficient information with respect to eNOS-mediated NO generation. Increases in eNOS in diabetic glomeruli observed by Hohenstein et al. are likely to reflect the pool of the enzyme that is not active in eNOS generation, but contributes to superoxide production. Clearly, a clinical study utilizing kidney biopsies cannot provide data reflecting the above-mentioned characteristics of eNOS. However, some determinants, in particular eNOS phosphorylation status, could be determined even in human biopsy material. We look forward to further clinical studies in this very important disease.
Conflict of interest statement. None declared.
Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR, USA
References
- Komers R, Anderson S. The paradoxes of nitric oxide in the diabetic kidney. Am J Physiol (2003) 284:F1121–F1137.[Web of Science]
- 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.
- Govers R, Rabelink TJ. Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol (2001) 280:F193–F206.
[Abstract/Free Full Text] - Komers R, Schutzer WE, Reed JF, et al. Altered endothelial nitric oxide synthase targeting and conformation and caveolin-1 expression in the diabetic kidney. Diabetes (2006) 55:1651–1659.
[Abstract/Free Full Text] - Satoh M, Fujimoto S, Haruna Y, et al. NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. Am J Physiol Renal Physiol (2005) 288:F1144–F1152.
[Abstract/Free Full Text]
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