Intrarenal renin-angiotensin system activation and urinary angiotensinogen as a novel biomarker of nephropathy in childhood
Intrarenal renin-angiotensin system activation plays a pivotal role in the pathogenesis of hypertension and chronic kidney disease. Recently, the focus of interest in the renin-angiotensin system has shifted toward the role of the local/tissue renin-angiotensin system in specific tissues. Angiotensi...
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| Published in | Japanese journal of pediatric nephrology Vol. 25; no. 2; pp. 121 - 126 |
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| Main Author | |
| Format | Journal Article |
| Language | Japanese |
| Published |
The Japanese Society for Pediatric Nephrology
2012
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0915-2245 1881-3933 1881-3933 |
| DOI | 10.3165/jjpn.25.121 |
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| Abstract | Intrarenal renin-angiotensin system activation plays a pivotal role in the pathogenesis of hypertension and chronic kidney disease. Recently, the focus of interest in the renin-angiotensin system has shifted toward the role of the local/tissue renin-angiotensin system in specific tissues. Angiotensinogen is the only known substrate for renin, which in the rate limiting enzyme of the renin-angiotensin system. Because the levels of angiotensinogen are close to the Michaelis-Menten constant values for renin, angiotensinogen levels as well as renin levels can control the renin-angiotensin system activity, and thus, up-regulation of angiotensinogen leads to an increase in the angiotensin II. While most circulating angiotensinogen is synthesized in the liver, the kidneys also produce angiotensinogen. Recent studies using experimental animal models have documented that involvement of angiotensinogen in the intrarenal renin-angiotensin system activation and development of hypertension and chronic kidney disease. Enhanced intrarenal angiotensinogen mRNA and/or protein levels were observed in those experimental models, supported the important roles of angiotensinogen in the development and the progression of the disease. Urinary excretion rates of angiotensinogen provide a specific index of the intrarenal renin-angiotensin system status. Using newly developed human angiotensinogen ELISA, we measured urinary angiotensinogen levels in chronic glomerulonephritis patients and patients with type 1 diabetes in childhood. Urinary angiotensinogen level was positively correlated with diastolic blood pressure, urinary albumin, urinary protein levels, and urinary occult blood in chronic glomerulonephritis patients. Furthermore, urinary angiotensinogen level was significantly increased in chronic glomerulonephritis patients not treated with renin-angiotensin system blockers compared with control subjects. Importantly, patients treated with renin-angiotensin blockers had a marked attenuation of this increase. Also, urinary angiotensinogen level was significantly higher in patients with diabetic nephropathy in the pre-micro albuminuric phase than in control subjects. These results suggest that urinary angiotensinogen reflects intrarenal renin-angiotensin system status in chronic glomerulonephritis and may be an early marker of diabetic nephropathy. |
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| AbstractList | Intrarenal renin-angiotensin system activation plays a pivotal role in the pathogenesis of hypertension and chronic kidney disease. Recently, the focus of interest in the renin-angiotensin system has shifted toward the role of the local/tissue renin-angiotensin system in specific tissues. Angiotensinogen is the only known substrate for renin, which in the rate limiting enzyme of the renin-angiotensin system. Because the levels of angiotensinogen are close to the Michaelis-Menten constant values for renin, angiotensinogen levels as well as renin levels can control the renin-angiotensin system activity, and thus, up-regulation of angiotensinogen leads to an increase in the angiotensin II. While most circulating angiotensinogen is synthesized in the liver, the kidneys also produce angiotensinogen. Recent studies using experimental animal models have documented that involvement of angiotensinogen in the intrarenal renin-angiotensin system activation and development of hypertension and chronic kidney disease. Enhanced intrarenal angiotensinogen mRNA and/or protein levels were observed in those experimental models, supported the important roles of angiotensinogen in the development and the progression of the disease. Urinary excretion rates of angiotensinogen provide a specific index of the intrarenal renin-angiotensin system status. Using newly developed human angiotensinogen ELISA, we measured urinary angiotensinogen levels in chronic glomerulonephritis patients and patients with type 1 diabetes in childhood. Urinary angiotensinogen level was positively correlated with diastolic blood pressure, urinary albumin, urinary protein levels, and urinary occult blood in chronic glomerulonephritis patients. Furthermore, urinary angiotensinogen level was significantly increased in chronic glomerulonephritis patients not treated with renin-angiotensin system blockers compared with control subjects. Importantly, patients treated with renin-angiotensin blockers had a marked attenuation of this increase. Also, urinary angiotensinogen level was significantly higher in patients with diabetic nephropathy in the pre-micro albuminuric phase than in control subjects. These results suggest that urinary angiotensinogen reflects intrarenal renin-angiotensin system status in chronic glomerulonephritis and may be an early marker of diabetic nephropathy. |
| Author | Urushihara, Maki |
| Author_xml | – sequence: 1 fullname: Urushihara, Maki organization: Department of Pediatrics, Institute of Health Biosciences, The University of Tokushima Graduate School |
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| References_xml | – reference: 35)Kobori H, Harrison-Bernard LM, Navar LG: Expression of angiotensinogen mRNA and protein in angiotensin II-dependent hypertension. J Am Soc Nephrol 2001; 12: 431-439. – reference: 46)Ohashi N, Katsurada A, Miyata K, Satou R, Saito T, Urushihara M, Kobori H: Activation of reactive oxygen species and the renin-angiotensin system in IgA nephropathy model mice. Clin Exp Pharmacol Physiol 2009; 36: 509-515. – reference: 67)Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-869. – reference: 54)Wolf G, Mueller E, Stahl RA, Ziyadeh FN: Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-beta. J Clin Invest 1993; 92: 1366-1372. – reference: 16)Moe OW, Ujiie K, Star RA, Miller RT, Widell J, Alpern RJ, Henrich WL: Renin expression in renal proximal tubule. J Clin Invest 1993; 91: 774-779. – reference: 32)Zhao YY, Zhou J, Narayanan CS, Cui Y, Kumar A: Role of C/A polymorphism at -20 on the expression of human angiotensinogen gene. Hypertension 1999; 33: 108-115. – reference: 60)Kobori H, Urushihara M, Xu JH, Berenson GS, Navar LG: Urinary angiotensinogen is correlated with blood pressure in men (Bogalusa Heart Study). J Hypertens 2010; 28: 1422-1428. – reference: 2)Dzau VJ, Re R: Tissue angiotensin system in cardiovascular medicine. A paradigm shift? Circulation 1994; 89: 493-498. – reference: 11)Ingelfinger JR, Zuo WM, Fon EA, Ellison KE, Dzau VJ: In situ hybridization evidence for angiotensinogen messenger RNA in the rat proximal tubule. An hypothesis for the intrarenal renin angiotensin system. J Clin Invest 1990; 85: 417-423. – reference: 55)Mifsud SA, Allen TJ, Bertram JF, Hulthen UL, Kelly DJ, Cooper ME, Wilkinson-Berka JL, Gilbert RE: Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade. Diabetologia 2001; 44: 878-882. – reference: 24)Brasier AR, Li J: Mechanisms for inducible control of angiotensinogen gene transcription. Hypertension 1996; 27: 465-475. – reference: 37)Kobori H, Nishiyama A, Abe Y, Navar LG: Enhancement of intrarenal angiotensinogen in Dahl salt-sensitive rats on high salt diet. Hypertension 2003; 41: 592-597. – reference: 42)Nagai Y, Yao L, Kobori H, Miyata K, Ozawa Y, Miyatake A, Yukimura T, Shokoji T, Kimura S, Kiyomoto H, Kohno M, Abe Y, Nishiyama A: Temporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats. J Am Soc Nephrol 2005; 16: 703-711. – reference: 10)Navar LG, Prieto-Carrasquero MC, Kobori H: Chapter 1: Molecular aspects of the renal renin-angiotensin system. 1st ed. Oxfordshine, UK, Taylor & Francis Medical, 2006: 3-14. – reference: 68)Haller H, Ito S, Izzo JL, Januszewicz A, Katayama S, Menne J, Mimran A, Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G; ROADMAP Trial Investigators: Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011; 364: 907-917. – reference: 19)Casarini DE, Boim MA, Stella RC, Krieger-Azzolini MH, Krieger JE, Schor N: Angiotensin I-converting enzyme activity in tubular fluid along the rat nephron. Am J Physiol 1997; 272: F405-409. – reference: 71)Wolkow PP, Niewczas MA, Perkins B, Ficociello LH, Lipinski B, Warram JH, Krolewski AS: Association of urinary inflammatory markers and renal decline in microalbuminuric type 1 diabetics. J Am Soc Nephrol 2008; 19: 789-797. – reference: 22)Navar LG, Harrison-Bernard LM, Nishiyama A, Kobori H: Regulation of intrarenal angiotensin II in hypertension. Hypertension 2002; 39: 316-322. – reference: 36)Kobori H, Harrison-Bernard LM, Navar LG: Enhancement of angiotensinogen expression in angiotensin II-dependent hypertension. Hypertension 2001; 37: 1329-1335. – reference: 59)Kobori H, Alper AB, Shenava R, Katsurada A, Saito T, Ohashi N, Urushihara M, Miyata K, Satou R, Hamm LL, Navar LG: Urinary angiotensinogen as a novel biomarker of the intrarenal renin-angiotensin system status in hypertensive patients. Hypertension 2009; 53: 344-350. – reference: 29)Merrill DC, Thompson MW, Carney CL, Granwehr BP, Schlager G, Robillard JE, Sigmund CD: Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes. 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| Title | Intrarenal renin-angiotensin system activation and urinary angiotensinogen as a novel biomarker of nephropathy in childhood |
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