Regulation of eNOS (Endothelial Nitric Oxide Synthase) in Nephrotic Syndrome Pathophysiology: Literature Review
DOI:
https://doi.org/10.33096/k5rq5d83Keywords:
Nephrotic syndrome, endothelial Nitric Oxide Synthase, vasodilation, blood pressure, endothelial cellAbstract
Introduction: Nephrotic syndrome (NS) is a chronic pediatric kidney disorder marked by proteinuria, edema, and impaired renal function, with eNOS-derived nitric oxide (NO) dysregulation implicated in its pathogenesis.
Methods: This literature review analyzed studies discussing the role of eNOS in the pathogenesis of NS, particularly steroid-sensitive nephrotic syndrome (SSNS) in pediatric patients. Relevant articles were identified from scientific databases using keywords related to nephrotic syndrome, eNOS, nitric oxide, and renal dysfunction. The selected studies included experimental, genetic, and clinical investigations evaluating eNOS expression, NO production, and associated renal outcomes. Data from the included studies were synthesized narratively to identify the relationship between eNOS dysregulation and NS progression.
Results: The reviewed studies demonstrated that eNOS-derived NO is essential for renal vasodilation, sodium excretion, and blood pressure regulation. Reduced eNOS activity and decreased NO availability were associated with proteinuria, sodium retention, edema, and hypertension in NS. Several studies reported that eNOS polymorphisms, including eNOS4a/b VNTR, were linked to lower plasma NO levels and progressive glomerular injury. Experimental models of NS also showed decreased eNOS and neuronal NOS expression, resulting in impaired natriuresis and renal dysfunction.
Conclusion: Dysregulation of the eNOS–NO pathway may contribute to NS through altered sodium handling, vascular tone, and blood pressure regulation. However, evidence is heterogeneous, with urinary NO metabolites, genetic polymorphisms, and tissue eNOS expression showing inconsistent patterns. Further pediatric studies are needed to clarify the relationship between eNOS, NO bioavailability, and clinical outcomes before eNOS-directed therapies can be recommended.
References
1. Duicu C, Tripon F, Crauciuc A, et al. Endothelial nitric oxide synthase gene polymorphisms and risk of nephrotic syndrome in children. Arch Dis Child. 2017;102:A50-A51.
2. Roy RR, Tonny RT, Akbar R, Sultana N, Ali A, Ray AK, et al. Clinicopathological spectrum and response pattern of adolescent-onset idiopathic nephrotic syndrome: are they different from young children? Paediatr Nephrol J Bangladesh. 2021;6(2):86-95. doi:10.4103/pnjb.pnjb_24_21.
3. Tapia C, Bashir K. Nephrotic syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
4. Chen G, Liu H, Liu F. A glimpse of the glomerular milieu: from endothelial cell to thrombotic disease in nephrotic syndrome. Microvasc Res. 2013;89:1-6. doi:10.1016/j.mvr.2013.06.011.
5. Niepolski L, Malinowska-Loba K. Association of circulating endothelial nitric oxide synthase levels with phosphataemia in patients on haemodialysis. Biomedicines. 2024;12(3):687. doi:10.3390/biomedicines12030687.
6. Alasehirli B, Balat A, Barlas O, Kont A. Nitric oxide synthase gene polymorphisms in children with minimal change nephrotic syndrome. Pediatr Int. 2009;51:75-78. doi:10.1111/j.1442-200X.2008.02655.x.
7. Tamura H. Trends in pediatric nephrotic syndrome. World J Nephrol. 2021;10(5):88-100. doi:10.5527/wjn.v10.i5.88.
8. Navasardyan I, Bonavida B. Regulation of T cells in cancer by nitric oxide. Cells. 2021;10(10):2655. doi:10.3390/cells10102655.
9. Niedbala W, Cai B, Liew FY. Role of nitric oxide in the regulation of T cell functions. Ann Rheum Dis. 2006;65(Suppl 3):iii37-iii40. doi:10.1136/ard.2006.058446.
10. Carlström M. Nitric oxide signalling in kidney regulation and cardiometabolic health. Nat Rev Nephrol. 2021;17(9):575-590. doi:10.1038/s41581-021-00429-z.
11. Ni Z, Vaziri ND. Downregulation of nitric oxide synthase in nephrotic syndrome: role of proteinuria. Biochim Biophys Acta. 2003;1638(2):129-137. doi:10.1016/S0925-4439(03)00061-9.
12. Tran N, Garcia T, Aniqa M, Ali S, Ally A, Nauli SM. Endothelial nitric oxide synthase (eNOS) and the cardiovascular system: in physiology and in disease states. Am J Biomed Sci Res. 2022;15(2):153-177.
13. Zhou TB, Xu HL, Yin SS. Association between endothelial nitric oxide synthase Glu298Asp gene polymorphism and diabetic nephropathy susceptibility. Ren Fail. 2013;35(1):173-178. doi:10.3109/0886022X.2012.734939.
14. Ray EC, Rondon-Berrios H, Boyd CR, Kleyman TR. Sodium retention and volume expansion in nephrotic syndrome: implications for hypertension. Adv Chronic Kidney Dis. 2015;22(3):179-184. doi:10.1053/j.ackd.2014.11.006.
15. Pitt B, Byington RP, Furberg CD, et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000;102(13):1503-1510. doi:10.1161/01.CIR.102.13.1503.
16. Hackl A, et al. The role of the immune system in idiopathic nephrotic syndrome. Mol Cell Pediatr. 2021;8(1). doi:10.1186/s40348-021-00128-6.
17. Mount PF, Power DA. Nitric oxide in the kidney: functions and regulation of synthesis. Acta Physiol. 2006;187:433-446. doi:10.1111/j.1748-1716.2006.01582.x.
18. Bae EH, Kim SW. Changes in endothelin receptor type B and neuronal nitric oxide synthase in puromycin aminonucleoside-induced nephrotic syndrome. Korean J Physiol Pharmacol. 2010;14(4):223-228. doi:10.4196/kjpp.2010.14.4.223.
19. Elmougy R. Genetic studies of nephrotic syndrome in Egyptian children. J Appl Biomed. 2021;19(4):228-233. doi:10.32725/jab.2021.022.
20. Ciuntu A. Role of metabolites of nitric oxide and arginase in the pathogenesis of glomerulonephritis. Curr Health Sci J. 2016;42(3):221-225. doi:10.12865/CHSJ.42.03.01.
21. Kameritsch P, et al. The mitochondrial thioredoxin reductase system (TrxR2) in vascular endothelium controls peroxynitrite levels and tissue integrity. Proc Natl Acad Sci U S A. 2021;118(7):e1921828118
