Abstract
Several lines of evidence suggest that angiotensin II (A-II) participates in the postnatal development of the kidney in rats. Many effects of A-II are mediated by mitogen-activated protein kinase (MAPK) pathways. This study investigated the influence that treatment with losartan during lactation has on MAPKs and on A-II receptor types 1 (AT1) and 2 (AT2) expression in the renal cortices of the offspring of dams exposed to losartan during lactation. In addition, we evaluated the relationship between such expression and changes in renal function and structure. Rat pups from dams receiving 2% sucrose or losartan diluted in 2% sucrose (40 mg/dl) during lactation were killed 30 days after birth, and the kidneys were removed for histological, immunohistochemical, and Western blot analysis. AT1 and AT2 receptors and p-p38, c-Jun N-terminal kinases (p-JNK) and extracellular signal-regulated protein kinases (p-ERK) expression were evaluated using Western blot analysis. The study-group rats presented an increase in AT2 receptor and MAPK expression. In addition, these rats also presented lower glomerular filtration rate (GFR), greater albuminuria, and changes in renal structure. In conclusion, newborn rats from dams exposed to losartan during lactation presented changes in renal structure and function, which were associated with AT2 receptor and MAPK expression in the kidneys.
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Nigam SK, Aperia AC, Brenner BM (1996) Development and maturation of the kidney. In: Brenner BM, Rector FC (eds) The kidney: physiology and pathology, 5th edn. WB Saunders, Philadelphia pp 72–98
Reeves W, Caulfield JP, Farquhar MG (1978) Differentiation of epithelial foot processes and filtration slits: sequential appearance of occluding junctions, epithelial polyanion and slit membranes in developing glomeruli. Lab Invest 39:90–100
Roberts AB, McCune BK, Sporn MB (1992) TGF-b: Regulation of extracellular matrix. Kidney Int 41:557–559
Thiery JP, Duband JL, Dufour S, Savagner P, Imhof BA (1989) Role of fibronectins in embryogenesis. In: Mosher DF (ed) Biology of extracellular matrix: fibronectin. Academic Press, Inc, San Diego, pp 181–212
Kagami S, Border WA, Miller DE, Noble NA (1994) 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
Bagby SP, Holden W (1988) Angiotensin II stimulates proliferation of aortic endothelial cells. Clin Res 36:259A
Woolf AS, Winyard PJ (1998) Advances in the cell biology and genetics of human kidney malformations. J Am Soc Nephrol 9:1114–1125
Gomez RA, Lynch KR, Sturgill BC, Elwood JP, Chevalier RL, Carey RM, Peach MJ (1989) Distribution of renin mRNA and its protein in the developing kidney. Am J Physiol 257:F850–F858
Gomez RA, Tufro-McReddie A, Everett AD, Pentz ES (1993) Ontogeny of renin and AT1 receptor in the rat. Pediatr Nephrol 7:635–638
Millan MA, Carvallo P, Izumi S, Zemel S, Catt KJ, Aguilera G (1989) Novel sites of expression of functional angiotensin II receptors in the late gestation fetus. Science 244:1340–1342
Tufro-McReddie A, Harrison JK, Everett AD, Gomez RA (1993) Ontogeny of angiotensin II type 1 receptor gene expression in the rat. J Clin Invest 91:530–537
Grady EF, Sechi LA, Griffin CA, Schambelan M, Kalinyak JE (1991) Expression of AT2 receptors in the development rat fetus. J Clin Invest 88:921–933
Yosypiv IV, Schroeder M, El-Dahr SS (2006) Angiotensin II type 1 receptor-EGF receptor cross-talk regulates ureteric bud branching morphogenesis. J Am Soc Nephrol 17:1005–1014
Bokemeyer D, Sorokin A, Dunn MJ (1996) Multiple intracellular MAP kinase signaling cascades. Kidney Int 49:1187–1198
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK- p38 MAP kinases on apoptosis. Science 270:1326–1331
Omori S, Hida M, Ishikura K, Kuramochi S, Awazu M (2000) Expression of mitogen-activated protein kinase family in rat renal development. Kidney Int 58:27–37
Kubo T, Ibusuki T, Chiba S, Kambe T, Fukumori R (2001) Mitogen activated protein kinase activity regulation role of angiotensin and endothelin systems in vascular smooth muscle cells. Eur J Pharmacol 411:27–34
Kumar D, Menon V, Ford WR, Clanachan AS, Jugdutt BI (2004) Effect of angiotensin II type 2 receptor blockade on mitogen activated protein kinases during myocardial ischemia-reperfusion. Mol Cell Biochem 258:211–218
Choi BM, Yoo KH, Bae IS, Oh MH, Hong YS, Lee JW, Kim SK (2005) Angiotensin II-converting enzyme inhibition modulates mitogenic-activated protein kinase family expressions in the neonatal rat kidney. Pediatr Res 57:115–123
Spence SG, Zacchei AG, Lee LL, Baldwin CL, Berna RA, Mattson BA, Eydelloth RS (1996) Toxicokinetic analysis of losartan during gestation and lactation in the rat. Teratology 53:245–252
Spence SG, Allen HL, Cukierski MA, Manson JM, Robertson RT, Eydelloth RS (1995) Defining the susceptible period of developmental toxicity for AT(1)-selective angiotensin-II receptor antagonist losartan in rats. Teratology 51:367–382
Coimbra TM, Janssen U, Grone HJ, Ostendorf T, Kunter U, Schmidt H, Brabant G, Floege J (2000) Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes. Kidney Int 57:167–182
Kliem V, Johnson RJ, Alpers CE, Yoshimura A, Couser WG, Koch KM, Floege J (1996) Mechanism involved in the pathogenesis of tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int 49:666–678
Stambe C, Atkins RC, Hill PA, Nikolic-Paterson DJ (2003) Activation and cellular localization of the p38 and JNK MAPK pathways in rat crescentic glomerulonephritis. Kidney Int 64:2121–2132
Hartree EF (1972) Determination of protein: a modification of the Lowry method that gives a linear photometric response. Anal Biochem 48:422–427
Haugen HN (1953) The determination of endogenous creatinine in plasma and urine. Scand J Clin Lab Invest 5:48–57
Laurell CB (1972) Electroimmunoassay. Scand J Clin Lab Invest 124(Suppl 1):21–37
Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501
Johren O, Dendorfer A, Dominiak P (2004) Cardiovascular and renal function of angiotensin II type 2 receptors. Cardiovasc Res 62:460–467
Coles HS, Burne JF, Raff MC (1993) Large-scale normal cell death in the developing rat kidney and its reduction by epidermal growth factor. Development 118:777–784
Akil I, Inan S, Gurcu B, Nazikoglu A, Ozbilgin K, Muftuoglu S (2005) Histopathological and ultrastructural effects of Losartan on embrionic rat kidney. Acta Histochem 107:291–300
Saward L, Zahradka P (1996) The angiotensin type 2 receptor mediates RNA synthesis in A10 vascular smooth muscle cells. J Mol Cell Cardiol 28:499–506
Friberg P, Sundelin B, Bohman SO, Bobik A, Nilsson H, Wickman A, Gustafsson H, Petersen J, Adams MA (1994) Renin-angiotensin system in neonatal rats-induction of renal abnormality in response to ACE-inhibition or angiotensin-II antagonism. Kidney Int 45:485–492
Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ (1998) Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 339:1285–1292
Tan Y, Wang B, Kuem JS, Jaffa AA (2005) Mechanisms of bradykinin induced glomerular injury in diabetes. Am J Physiol Renal Physiol 288:F483–F492
Brooks DP, Ruffolo RR Jr (1999) Pharmacological mechanism of angiotensin II receptor antagonists: implications for the treatment of elevated systolic blood pressure. J Hypertens Suppl 17:S27–32
Yang D, Tournier C, Wysk M, Lu HT, Xu J, Davis RJ, Flavell RA (1997) Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation and defects in AP-1 transcriptional activity. Proc Natl Acad Sci USA 94:3004–3009
Francescato HDC, Costa RS, Barbosa Jr F, Coimbra TM (2007) Effect of JNK inhibition on cisplatin-induced renal damage. Nephrol Dial Transplant 22:2138–2148
Nath P, Eynott P, Leung S-Y, Adcock IM, Bennett BL, Chung KF (2005) Potential role of c-Jun NH2-terminal kinase in allergic airway inflammation and remodeling: effects of SP600125. Eur J Pharmacol 506:273–283
Kumar S, Boehm J, Lee JC (2003) P38 MAP kinases: Key signaling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2:717–726
Ferrandi C, Ballerio R, Gaillard P, Giachetti C, Carboni S, Vitte P-A, Gotteland J-P, Cirillo R (2004) Inhibition of c-jun-N-terminal kinase decreases cardiomyocyte apoptosis and infarct size after myocardial ischemia and reperfusion in anaesthetized rats. Br J Pharmacol 142:953–960
Naruse K, Fujieda M, Miyazaki E, Hayashi Y, Toi M, Fukui T, Kuroda N, Hiroi M, Kurashige T, Enzan H (2000) An immunohistochemical study of developing glomeruli in human fetal kidneys. Kidney Int 57:1836–1846
El Nahas AM, Muchaneta-Kubara EC, Zhang G, Adam A, Goumenos D (1996) Phenotypic modulation of renal cells during experimental and clinical renal scarring. Kidney Int 54:S23–S27
Eddy AA (2000) Molecular basis of renal fibrosis. Pediatr Nephrol 15:290–301
Chen Y, Lasaitiene D, Gabrielsson BG, Carlsson LM, Billig H, Carlsson B, Marcussen N, Sun XF, Friberg P (2004) Neonatal Losartan treatment suppresses renal expression of molecules involved in cell-cell and cell-matrix interactions. J Am Soc Nephrol 15:1232–1243
Acknowledgements
Financial support was provided in the form of a grant from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Foundation for the Support of Research in the state of São Paulo). The authors are grateful to Cleonice G. A. da Silva, Adriana L. G. de Almeida, and Erica Delloiagono for technical assistance.
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Balbi, A.P.C., Marin, E.C.S., Francescato, H.D.C. et al. MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams. Pediatr Nephrol 23, 1433–1444 (2008). https://doi.org/10.1007/s00467-008-0830-1
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DOI: https://doi.org/10.1007/s00467-008-0830-1