Top

Published in:

01-06-2015 | Original Article

Changes in urinary angiotensinogen posttreatment in pediatric IgA nephropathy patients

Authors: Maki Urushihara, Takashi Nagai, Yukiko Kinoshita, Sato Nishiyama, Kenichi Suga, Natsuko Ozaki, Ariunbold Jamba, Shuji Kondo, Hiroyuki Kobori, Shoji Kagami

Published in: Pediatric Nephrology | Issue 6/2015

Abstract

Background

Recently, we demonstrated that urinary angiotensinogen (AGT) levels are increased and reflect intrarenal renin–angiotensin system (RAS) status in pediatric patients with chronic glomerulonephritis. Therefore, this study was performed to test the hypothesis that urinary AGT (UAGT) levels provide a specific index of intrarenal RAS status associated with RAS blockade treatment in pediatric IgA nephropathy (IgAN) patients.

Methods

We measured plasma and UAGT levels and urinary transforming growth factor beta (TGF-β) levels, after which we performed immunohistochemical analysis of AGT, angiotensin II (Ang II), and TGF-β in 24 pediatric IgAN patients treated with RAS blockades for 2 years. Paired tests were used to analyze the changes from baseline to study end.

Results

Although there was no change in plasma AGT levels, UAGT and TGF-β levels were significantly decreased after RAS blockade, which was accompanied by the expression levels of AGT, Ang II, and TGF-β, as well as the magnitude of glomerular injury. Baseline UAGT levels positively correlated with diastolic blood pressure, urinary protein levels, scores for mesangial hypercellularity, and the expression levels of AGT, Ang II, and TGF-β in renal tissues.

Conclusions

These data indicate that UAGT is a useful biomarker of intrarenal RAS activation, which is associated with glomerular injury during RAS blockade in pediatric IgAN patients.

Kobori H, Urushihara M (2013) Augmented intrarenal and urinary angiotensinogen in hypertension and chronic kidney disease. Pflugers Arch 465:3–12PubMedCentralPubMed

Dzau VJ, Re R (1994) Tissue angiotensin system in cardiovascular medicine. A paradigm shift. Circulation 89:493–498CrossRefPubMed

Navar LG, Harrison-Bernard LM, Nishiyama A, Kobori H (2002) Regulation of intrarenal angiotensin II in hypertension. Hypertension 39:316–322CrossRefPubMedCentralPubMed

Baltatu O, Silva JA Jr, Ganten D, Bader M (2000) The brain renin-angiotensin system modulates angiotensin II-induced hypertension and cardiac hypertrophy. Hypertension 35:409–412CrossRefPubMed

Dell’Italia LJ, Meng QC, Balcells E, Wei CC, Palmer R, Hageman GR, Durand J, Hankes GH, Oparil S (1997) Compartmentalization of angiotensin II generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces. J Clin Invest 100:253–258CrossRefPubMedCentralPubMed

Danser AH, Admiraal PJ, Derkx FH, Schalekamp MA (1998) Angiotensin I-to-II conversion in the human renal vascular bed. J Hypertens 16:2051–2056CrossRefPubMed

Kobori H, Nangaku M, Navar LG, Nishiyama A (2007) The intrarenal renin-angiotensin system: From physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59:251–287CrossRefPubMed

Katsurada A, Hagiwara Y, Miyashita K, Satou R, Miyata K, Ohashi N, Navar LG, Kobori H (2007) Novel sandwich ELISA for human angiotensinogen. Am J Physiol Renal Physiol 293:F956–960CrossRefPubMedCentralPubMed

Kobori H, Alper AB Jr, Shenava R, Katsurada A, Saito T, Ohashi N, Urushihara M, Miyata K, Satou R, Hamm LL, Navar LG (2009) Urinary angiotensinogen as a novel biomarker of the intrarenal renin-angiotensin system status in hypertensive patients. Hypertension 53:344–350CrossRefPubMedCentralPubMed

10.

Kobori H, Urushihara M, Xu JH, Berenson GS, Navar LG (2010) Urinary angiotensinogen is correlated with blood pressure in men (Bogalusa Heart Study). J Hypertens 28:1422–1428CrossRefPubMedCentralPubMed

11.

Kobori H, Ohashi N, Katsurada A, Miyata K, Satou R, Saito T, Yamamoto T (2008) Urinary angiotensinogen as a potential biomarker of severity of chronic kidney diseases. J Am Soc Hypertens 2:349–354CrossRefPubMedCentralPubMed

12.

Urushihara M, Kondo S, Kagami S, Kobori H (2010) Urinary angiotensinogen accurately reflects intrarenal Renin-Angiotensin system activity. Am J Nephrol 31:318–325CrossRefPubMedCentralPubMed

13.

Saito T, Urushihara M, Kotani Y, Kagami S, Kobori H (2009) Increased urinary angiotensinogen is precedent to increased urinary albumin in patients with type 1 diabetes. Am J Med Sci 338:478–480CrossRefPubMedCentralPubMed

14.

Sawaguchi M, Araki SI, Kobori H, Urushihara M, Haneda M, Koya D, Kashiwagi A, Uzu T, Maegawa H (2012) Association between urinary angiotensinogen levels and renal and cardiovascular prognoses in patients with type 2 diabetes mellitus. J Diabetes Investig 3:318–324CrossRefPubMedCentralPubMed

15.

Roberts IS, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, Cattran DC, Coppo R, D’Agati V, D’Amico G, Emancipator S, Emma F, Feehally J, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H (2009) The Oxford classification of IgA nephropathy: Pathology definitions, correlations, and reproducibility. Kidney Int 76:546–556CrossRefPubMed

16.

Yoshikawa N, Iijima K, Maehara K, Yoshiara S, Yoshiya K, Matsuo T, Okada S (1987) Mesangial changes in IgA nephropathy in children. Kidney Int 32:585–589CrossRefPubMed

17.

Takamatsu M, Urushihara M, Kondo S, Shimizu M, Morioka T, Oite T, Kobori H, Kagami S (2008) Glomerular angiotensinogen protein is enhanced in pediatric IgA nephropathy. Pediatr Nephrol 23:1257–1267CrossRefPubMedCentralPubMed

18.

Fukuda M, Urushihara M, Wakamatsu T, Oikawa T, Kobori H (2012) Proximal tubular angiotensinogen in renal biopsy suggests nondipper BP rhythm accompanied by enhanced tubular sodium reabsorption. J Hypertens 30:1453–1459CrossRefPubMedCentralPubMed

19.

Tanaka H, Suzuki K, Nakahata T, Tsugawa K, Konno Y, Tsuruga K, Ito E, Waga S (2004) Combined therapy of enalapril and losartan attenuates histologic progression in immunoglobulin A nephropathy. Pediatr Int 46:576–579CrossRefPubMed

20.

Yang Y, Ohta K, Shimizu M, Nakai A, Kasahara Y, Yachie A, Koizumi S (2005) Treatment with low-dose angiotensin-converting enzyme inhibitor (ACEI) plus angiotensin II receptor blocker (ARB) in pediatric patients with IgA nephropathy. Clin Nephrol 64:35–40CrossRefPubMed

21.

Ballardie FW, Roberts IS (2002) Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. J Am Soc Nephrol 13:142–148PubMed

22.

Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D’Agati V, D’Amico G, Emancipator S, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Leung CB, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H (2009) The Oxford classification of IgA nephropathy: Rationale, clinicopathological correlations, and classification. Kidney Int 76:534–545CrossRefPubMed

23.

Kobori H, Katsurada A, Ozawa Y, Satou R, Miyata K, Hase N, Suzaki Y, Shoji T (2007) Enhanced intrarenal oxidative stress and angiotensinogen in IgA nephropathy patients. Biochem Biophys Res Commun 358:156–163CrossRefPubMedCentralPubMed

24.

Nishiyama A, Konishi Y, Ohashi N, Morikawa T, Urushihara M, Maeda I, Hamada M, Kishida M, Hitomi H, Shirahashi N, Kobori H, Imanishi M (2011) Urinary angiotensinogen reflects the activity of intrarenal renin-angiotensin system in patients with IgA nephropathy. Nephrol Dial Transplant 26:170–177CrossRefPubMedCentralPubMed

25.

Kim YG, Song SB, Lee SH, Moon JY, Jeong KH, Lee TW, Ihm CG (2011) Urinary angiotensinogen as a predictive marker in patients with immunoglobulin A nephropathy. Clin Exp Nephrol 15:720–726CrossRefPubMed

26.

Jang HR, Kim SM, Lee YJ, Lee JE, Huh W, Kim DJ, Oh HY, Kim YG (2012) The origin and the clinical significance of urinary angiotensinogen in proteinuric IgA nephropathy patients. Ann Med 44:448–457CrossRefPubMed

27.

Ingelfinger JR, Zuo WM, Fon EA, Ellison KE, Dzau VJ (1990) In situ hybridization evidence for angiotensinogen messenger RNA in the rat proximal tubule. An hypothesis for the intrarenal renin angiotensin system. J Clin Invest 85:417–423CrossRefPubMedCentralPubMed

28.

Lantelme P, Rohrwasser A, Gociman B, Hillas E, Cheng T, Petty G, Thomas J, Xiao S, Ishigami T, Herrmann T, Terreros DA, Ward K, Lalouel JM (2002) Effects of dietary sodium and genetic background on angiotensinogen and Renin in mouse. Hypertension 39:1007–1014CrossRefPubMed

29.

Rohrwasser A, Morgan T, Dillon HF, Zhao L, Callaway CW, Hillas E, Zhang S, Cheng T, Inagami T, Ward K, Terreros DA, Lalouel JM (1999) Elements of a paracrine tubular renin-angiotensin system along the entire nephron. Hypertension 34:1265–1274CrossRefPubMed

30.

Nakano D, Kobori H, Burford JL, Gevorgyan H, Seidel S, Hitomi H, Nishiyama A, Peti-Peterdi J (2012) Multiphoton imaging of the glomerular permeability of angiotensinogen. J Am Soc Nephrol 23:1847–1856CrossRefPubMedCentralPubMed

31.

Ohashi N, Urushihara M, Satou R, Kobori H (2010) Glomerular angiotensinogen is induced in mesangial cells in diabetic rats via reactive oxygen species–ERK/JNK pathways. Hypertens Res 33:1174–1181CrossRefPubMedCentralPubMed

32.

Brunner HR (1992) ACE inhibitors in renal disease. Kidney Int 42:463–479CrossRefPubMed

33.

Lafayette RA, Mayer G, Park SK, Meyer TW (1992) Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 90:766–771CrossRefPubMedCentralPubMed

34.

Kohan DE (1998) Angiotensin II and endothelin in chronic glomerulonephritis. Kidney Int 54:646–647CrossRefPubMed

35.

Urushihara M, Kinoshita Y, Kondo S, Kagami S (2012) Involvement of the intrarenal renin-angiotensin system in experimental models of glomerulonephritis. J Biomed Biotechnol 2012:601786CrossRefPubMedCentralPubMed

36.

Johnson RJ, Iida H, Alpers CE, Majesky MW, Schwartz SM, Pritzi P, Gordon K, Gown AM (1991) Expression of smooth muscle cell phenotype by rat mesangial cells in immune complex nephritis. Alpha-smooth muscle actin is a marker of mesangial cell proliferation. J Clin Invest 87:847–858CrossRefPubMedCentralPubMed

37.

Gomez-Garre D, Ruiz-Ortega M, Ortego M, Largo R, Lopez-Armada MJ, Plaza JJ, Gonzalez E, Egido J (1996) Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. Hypertension 27:885–892CrossRefPubMed

38.

Minutolo R, Balletta MM, Catapano F, Chiodini P, Tirino G, Zamboli P, Fuiano G, Russo D, Marotta P, Iodice C, Conte G, De Nicola L (2006) Mesangial hypercellularity predicts antiproteinuric response to dual blockade of RAS in primary glomerulonephritis. Kidney Int 70:1170–1176CrossRefPubMed

39.

Border WA, Noble NA (1994) Transforming growth factor-beta in glomerular injury. Exp Nephrol 2:13–17PubMed

40.

Kagami S, Border WA, Miller DE, Noble NA (1994) Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest 93:2431–2437CrossRefPubMedCentralPubMed

41.

Urushihara M, Ohashi N, Miyata K, Satou R, Acres OW, Kobori H (2011) Addition of angiotensin II type 1 receptor blocker to CCR2 antagonist markedly attenuates crescentic glomerulonephritis. Hypertension 57:586–593CrossRefPubMedCentralPubMed

Title: Changes in urinary angiotensinogen posttreatment in pediatric IgA nephropathy patients
Authors: Maki Urushihara
Takashi Nagai
Yukiko Kinoshita
Sato Nishiyama
Kenichi Suga
Natsuko Ozaki
Ariunbold Jamba
Shuji Kondo
Hiroyuki Kobori
Shoji Kagami
Publication date: 01-06-2015
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 6/2015
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-014-3028-8

At a glance: The STEP trials

Springer Medicine

Changes in urinary angiotensinogen posttreatment in pediatric IgA nephropathy patients

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2015

Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome

Acidosis: progression of chronic kidney disease and quality of life

Cystinosis: renal glomerular and renal tubular function in relation to compliance with cystine-depleting therapy

A case of C3 glomerulonephritis successfully treated with eculizumab

When listening for hoofbeats, sometimes there are zebras—an interesting case of a teenager with edema and high blood pressure: Questions

Peri-operative kidney injury and long-term chronic kidney disease following orthotopic heart transplantation in children