The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Upregulation of Renal Renin-Angiotensin System in Rats with Adriamycin-Induced Nephrosis

  • Kim, Soo-Wan (Chonnam National University Research Institute of Medical Sciences) ;
  • Lee, Jong-Un (Chonnam National University Research Institute of Medical Sciences) ;
  • Han, Sang-Woong (Department of Internal Medical, Hanyang University) ;
  • Ryu, Jun-Ho (Department of Internal Medical, Hanyang University) ;
  • Oh, Yoon-Wha (Chonnam National University Research Institute of Medical Sciences) ;
  • Kim, Nam-Ho (Chonnam National University Research Institute of Medical Sciences) ;
  • Choi, Ki-Chul (Chonnam National University Research Institute of Medical Sciences) ;
  • Kim, Ho-Jung (Department of Internal Medical, Hanyang University)
  • Published : 2002.04.21
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Abstract

The present study was aimed to investigate whether the adriamycin-induced nephrosis is associated with an altered regulation of local renin-angiotensin system (RAS) in the kidney. Rats were subjected to a single injection of adriamycin (2 mg/kg body weight, IV) and kept for 6 weeks to allow the development of nephrosis. They were then divided into two groups, and supplied with and without cilazapril, an angiotensin converting enzyme (ACE) inhibitor, in drinking water (100 mg/l) for additional 6 weeks. Another group without adriamycin-treatment served as control. The mRNA expression of renin, ACE, type 1 and type 2 angiotensin II receptors (AT1R, AT2R), and transforming growth factor $(TGF)-{\beta}1$ was determined in the cortex of the kidney by reverse transcription-polymerase chain reaction. Adriamycin treatment resulted in heavy proteinuria. Accordingly, the mRNA expression of renin, ACE, and AT1R was increased in the renal cortex, while that of AT2R was decreased. Co-treatment with cilazapril attenuated the degree of proteinuria. While not affecting the altered expression of renin, cilazapril decreased the expression of ACE to the control level. Cilazapril further increased the expression of AT1R, while it restored the decreased expression of AT2R. The expression of $(TGF)-{\beta}1$ was increased by the treatment with adriamycin, which was abolished by cilazapril. An altered expression of local RAS components may be causally related with the development of adriamycin-induced nephrosis, in which AT1R is for and AT2R is against the development of nephrosis.

Keywords

References

  1. Anderson S. Physiologic actions and molecular expression of the renin-angiotensin system in the diabetic rat. Miner Electrolyte Metab 24: 406－411, 1998 https://doi.org/10.1159/000057402
  2. Anderson S, Rennke HG, Brenner BM. Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest 77: 1993－2000, 1986 https://doi.org/10.1172/JCI112528
  3. Arima S, Endo Y, Yaoita H, Omata K, Ogawa S, Tsunoda K, Abe M, Takeuchi K, Abe K, Ito S. Arima S, Endo Y, Yaoita H, Omata K, Ogawa S, Tsunoda K, Abe M, Takeuchi K, Abe K, Ito S. Possible role of P-450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in the isolated microperfused rabbit afferent arteriole. J Clin Invest 100: 2816－2823, 1997 https://doi.org/10.1172/JCI119829
  4. Endo Y, Arima S, Yaoita H, Tsunoda K, Omata K, Ito S. Vasodilation mediated by angiotensin II type 2 receptor is impaired in afferent arterioles of young spontaneously hypertensive rats. J Vasc Res 35: 421－427, 1998 https://doi.org/10.1159/000025613
  5. Fukuda K, Yoshitomi K, Yanagida T, Tokumoto M, Hirakata H. Quantification of TGF-$\beta$1 mRNA along rat nephron in obstructive nephropathy. Am J Physiol 281: F513－F521, 2001
  6. Gasc JM, Monnot C, Clauser E, Corvol P. Co-expression of type I angiotensin II receptor (AT1R) and rennin mRNAs in juxtaglomerular cells of rat kidney. Endocrinology 132: 2723－ 2725, 1993 https://doi.org/10.1210/en.132.6.2723
  7. Gomez RA, Lynch KR, Chevalier RL, Everett AD, Johns DW, Wilfong N, Peach MJ, Carey RM. Renin and angiotensinogen gene expression and intrarenal renin distribution during ACE inhibition. Am J Physiol 254: F900－F906, 1988
  8. Hall RL, Wilke WL, Fettman MJ. The progression of adriamycininduced nephritic syndrome in rats and the effect of captopril. Toxicol Appl Pharmacol 82: 164－174, 1986 https://doi.org/10.1016/0041-008X(86)90448-5
  9. Hirsch AT, Talsness CE, Smith AD, Schunkert H, Ingelfinger JR, Dzau VJ. Differential effects of captopril and enalapril on tissue rennin-angiotensin systems in experimental heart failure. Circulation 86: 1566－1574, 1992 https://doi.org/10.1161/01.CIR.86.5.1566
  10. Hunley TE, Tamura M, Stoneking BJ, Nishimura H, Ichiki T, Inagami T, Kon V. The angiotensin type II receptor tonically inhibits angiotensin-converting enzyme in AT2 null mutant mice. Kidney Int 57: 570－577, 2000 https://doi.org/10.1046/j.1523-1755.2000.00877.x
  11. Kagami S, Border WA, Miller DE, Noble NA. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-b expression in rat glomerular mesangial cells. J Clin Invest 93: 2431－2437, 1994 https://doi.org/10.1172/JCI117251
  12. Kakinuma Y, Kawamura T, Bills T, Yoshioka T, Ichikawa I, Fogo A. Blood pressure-independent effect of angiotensin inhibition on vascular lesions of chronic renal failure. Kidney Int 42: 46－ 55, 1992 https://doi.org/10.1038/ki.1992.259
  13. Kastner PR, Hall JE, Guyton AC. Control of glomerular filtration rate: Role of intrarenally formed angiotensin II. Am J Physiol 246: F897－F906, 1984
  14. Kitami Y, Okura T, Marumoto K, Wakamiya R, Hiwada K. Differential gene expression and regulation of type-1 angiotensin II receptor subtypes in the rat. Biochem Biophys Res Commun 188: 446－452, 1992 https://doi.org/10.1016/0006-291X(92)92405-M
  15. Lafayette RA, Mayer G, Park SK, Meyer TW. Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 90: 766－771, 1992 https://doi.org/10.1172/JCI115949
  16. Li J, Zhou C, Yu L, Wang H. Renal protective effects of blocking the intrarenal renin-angiotensin system. Hypertens Res 22: 223 －228, 1999 https://doi.org/10.1291/hypres.22.223
  17. Mistry SK, Chatterjee PK, Weerackody RP, Hawksworth GM, Knott RM, McLay JS. Evidence for atrial natriuretic factor induced natriuretic peptide receptor subtype switching in rat proximal tubular cells during cell culture. Exp Nephrol 6: 101－ 111, 1998
  18. Miyata N, Park F, Li XF, Cowley AW Jr. Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney. Am J Physiol 277: F437－F446, 1999
  19. Nakamura N, Soubrier F, Menard J, Panthier JJ, Rougeon F, Corvol P. Nonproportional changes in plasma renin concentration, renal renin content, and rat renin messenger RNA. Hypertension 7: 855－859, 1989
  20. Nakamura T, Obata J, Kimura H, Ohno S, Yoshida Y, Kawachi H, Shimizu F. Blocking angiotensin II ameliorates proteinuria and glomerular lesions in progressive mesangioproliferative glomerulonephritis. Kidney Int 55: 877－889, 1999 https://doi.org/10.1046/j.1523-1755.1999.055003877.x
  21. Neimir Z, Stein H, Noronha I, Kruger C, Andrassy K, Ritz E, Waldherr R. PDGF and TGF-$\beta$ contribute to the natural course of human IgA glomerulonephritis. Kidney Int 48: 1530－1541, 1995 https://doi.org/10.1038/ki.1995.443
  22. Negoro N, Kanayama Y, Iwai J, Umetani N, Nishimura M, Konishi Y, Okamura M, Inoue T, Takeda T. Angiotensin-converting enzyme inhibitor increases angiotensin type 1A receptor gene expression in aortic smooth muscle cells of spontaneously hypertensive rats. Biochim Biophys Acta 1226: 19－24, 1994
  23. Noble NA, Border WA. Angiotensin II in renal fibrosis: should TGF- $\beta$ rather than blood pressure be the therapeutic target. Semin Nephrol 17: 455－466, 1997
  24. Okuda S, Oh Y, Tsuruda H, Onoyama K, Fujimi S, Fujishima M. Adriamycin-induced nephropathy as a model of chronic progressive glomerular disease. Kidney Int 29: 502－510, 1986 https://doi.org/10.1038/ki.1986.28
  25. Passier RC, Smits JF, Verluyten MJ, Studer R, Drexler H, Daemen MJ. Activation of angiotensin converting enzyme expression in infarct zone following myocardial infarction. Am J Physiol 269: H1268－H1276, 1995
  26. Ruiz-Ortega M, Egido J. Angiotensin II modulates cell growthrelated events, and synthesis of matrix proteins in renal interstitial fibrosis. Kidney Int 52: 1497－1510, 1997 https://doi.org/10.1038/ki.1997.480
  27. Tank JE, Moe OW, Henrich WL. Abnormal regulation of proximal tubule renin mRNA in the Dahl/Rapp salt-sensitive rat. Kidney Int 54: 1608－16, 1998 https://doi.org/10.1046/j.1523-1755.1998.00160.x
  28. Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, Miyazaki M, Nozawa Y, Ozono R, Nakagawa K, Miwa T, Kawada N, Mori Y, Shibasaki Y, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Takahashi H, Iwasaka T. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest 104: 925－935, 1999 https://doi.org/10.1172/JCI7886
  29. Wolf G, Mueller E, Stahl RAK, Ziyadeh FN. Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-b. J Clin Invest 92: 1366－1372, 1993 https://doi.org/10.1172/JCI116710
  30. Wu LL, Cox A, Roe CJ, Dziadek M, Cooper ME, Gilbert RE. Transforming groth factor b1 and renal injury following subtotal nephrectomy in the rat: Role of the renin-angiotensin system. Kidney Int 51: 1553－1567, 1997 https://doi.org/10.1038/ki.1997.214
  31. Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci USA 90: 1814－1818, 1993 https://doi.org/10.1073/pnas.90.5.1814