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1 medicine, nymc, valhalla, New York, United States
2 Medicine- Renal Research Institute, New york medical college, Valhalla, New York, United States
3 medicine, nymc, valhalla, New York, United States; valhalla, New York, United States
4 biochemistry, cornell, new york, New York, United States
5 pathology, nymc, valhalla, New York, United States
6 Nephrology Division and Renal Research Institute, New York Medical College, Valhalla, New York, United States
* To whom correspondence should be addressed. E-mail: michael_goligorsky{at}nymc.edu.
Chronic kidney diseases are accompanied by the accumulation of substances like asymmetric dimethylarginine and phenylacetic acid, homocysteine, and advanced glycation end products, known to either inhibit endothelial nitric oxide synthase (eNOS) or uncouple it, consequently limiting the amount of available NO. Reduced bioavailability of NO is a cornerstone of the developing endothelial dysfunction. An early loss of peritubular capillaries in tubulointerstitial fibrotic areas and injury to endothelial cells have been linked to progressive renal disease. Screening endothelial genes in cells treated with NOS inhibitors showed upregulation of collagen XVIII, a precursor of a potent anti-angiogenic substance, endostatin. This finding was confirmed at the level of mRNA and protein expression. Tie-2/GFP mice treated with non-hypertensinogenic doses of a NOS inhibitor exhibited upregulation of collagen XVIII/endostatin and rarefaction of capillary profiles. This was accompanied by the increased expression of TGF-beta and CTGF in the kidney. Occasional endothelial cells expressed both the marker of endothelial lineage (GFP) and mesenchymal marker (
-SMA or calponin). In vitro studies of endothelial cells treated with asymmetric dimethylarginine showed decreased expression of eNOS and Flk-1 and enhanced expression of calponin and fibronectin, additional markers of smooth muscle/mesenchymal cells. These cells overexpressed TGF-
and CTGF, as well as endostatin. In conclusion, data presented here 1) ascribe to NO deficiency in endothelial cells the function of a profibrotic stimulus associated with the expression of an antiangiogenic fragment of collagen XVIII, endostatin; 2) provide evidence of endothelial-mesenchymal transdifferentiation in the course of inhibition of nitric oxide synthase by a pathophysiologically important antagonist, ADMA. Both mechanisms may account for microvascular rarefaction.
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