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Agmatine Inhibits Cell Proliferation and Improves Renal Function in Anti–Thy-1 Glomerulonephritis

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Agmatine Inhibits Cell Proliferation and Improves Renal Function in Anti–Thy-1 Glomerulonephritis J Am Soc Nephrol 11: 2256–2264, 2000 Agmatine Inhibits Cell Proliferation and Improves Renal Function in Anti–Thy-1 Glomerulonephritis SHUNJI ISHIZUKA, ROBYN CUNARD, SIRIA POUCELL-HATTON, LUCINDA WEAD, MARK LORTIE, SCOTT C. THOMSON, FRANCIS B. GABBAI, JOSEPH SATRIANO, AND ROLAND C. BLANTZ Division of Nephrology-Hypertension and Pathology, University of California, Department of Medicine, San Diego, and VA San Diego Healthcare System, La Jolla, California. Abstract. Changes in the expression of alternate arginine met- production in Thy-1 nephritis rats by 23% and 41% at days 1 abolic pathways have been implicated in the pathogenesis of and 4, respectively. Agmatine treatment also reduced ODC experimental glomerulonephritis. Agmatine, decarboxylated activity and glomerular 3H-thymidine incorporation on days 1, arginine, has been shown in vitro to suppress both inducible 4, and 7. Histologic evaluation revealed a decline in mesangial nitric oxide synthase and the rate-limiting enzyme of poly- cell proliferation and extracellular matrix accumulation asso- amine biosynthesis, ornithine decarboxylase (ODC). This ciated with agmatine treatment administered before or 24 h study was undertaken to determine whether agmatine admin- after Thy-1 antibody, and this was confirmed by a reduction in istration could reduce tissue injury by decreasing nitric oxide, the number of cells expressing proliferating cell nuclear anti- and reduce cell proliferation, by diminishing ODC activity, in gen on days 4 and 7. These studies provide the first in vivo experimental mesangial proliferative glomerulonephritis evidence that agmatine administration can reduce cellular pro- (Thy-1 nephritis). Agmatine treatment (50 mg/kg per d intra- liferation in Thy-1 nephritis and attenuate the initial reduction peritoneally) in Thy-1 nephritis rats prevented a reduction in in renal function associated with this model. GFR at day 1. Agmatine treatment decreased nitric oxide Two well-described pathways of L-arginine metabolism in extracellular matrix (3). Therefore, the production of ornithine inflammation include the conversion of arginine to nitric oxide and its subsequent metabolism to polyamines and proline are (NO) by nitric oxide synthase (NOS), and the breakdown of important elements of the repair phase. L-arginine to urea and L-ornithine by arginase. These path- A third arginine metabolic pathway, the conversion of argi- ways are temporally regulated in inflammatory models of nine to agmatine by arginine decarboxylase (ADC), has re- wound healing and glomerulonephritis (GN) (1,2). In the early cently been described in mammals (7). ADC activity is prev- injury phase of inflammation, there is induction of inducible alent in the kidney, liver, and brain. Similarly, agmatine is NOS (iNOS) expression and generation of NO (3–5). High- present in the plasma and has been observed in multiple tissues output NO generation from iNOS during periods of cellular and cell types (8–10). Agmatine exerts functional effects stress is known to exert cytostatic and cytotoxic effects. This is within the kidney, elevating single nephron filtration rate followed by the production of ornithine, which initiates the (SNGFR) via vasodilatation by constitutive NOS (cNOS) and repair phase (1). Ornithine is converted to polyamines via the ryanodine channel-dependent mechanisms (10,11). Agmatine rate-limiting polyamine biosynthetic enzyme, ornithine decar- also suppresses NO generation by iNOS in vitro (12,13; Satri- boxylase (ODC). Polyamines are required components of cell ano et al., submitted). Studies have recently shown that agma- cycle entry and progression and thus are essential for cellular proliferation (6). Ornithine is also metabolized by ornithine tine inhibits ODC activity and polyamine transport by an aminotransferase (OAT) to proline, an important constituent of ODC-antizyme–dependent mechanism (14). These data sug- gest that agmatine could exert important effects on both NO production and cell proliferation in inflammatory conditions. Received July 27, 1999. Accepted April 23, 2000. It is widely recognized that NO production is increased after Correspondence to Dr. Roland C. Blantz, Professor and Head, Division of induction of accelerated nephrotoxic-serum GN, active Hey- Nephrology-Hypertension, UCSD & VA Medical Center, 3350 La Jolla Vil- lage Drive, San Diego, CA 92161. Phone: 619-552-7528; Fax: 619-552-7549; mann GN, in situ immune complex GN, and anti–Thy-1 anti- E-mail: [email protected] body–induced GN (Thy-1 nephritis) (4,5,15). Thy-1 nephritis A portion of this work was presented at the annual meeting of the American is a model of acute mesangial proliferative GN in rats that is Society of Nephrology, 1998. characterized by early mesangial cell (MC) injury, followed by S.I. and R.C. share first-author status. MC proliferation (16,17). Augmentation of arginase activity 1046-6673/1112-2256 Journal of the American Society of Nephrology and ODC and OAT expression in the repair phase result in Copyright © 2000 by the American Society of Nephrology cellular proliferation and extracellular matrix production in this J Am Soc Nephrol 11: 2256–2264, 2000 Effects of Agmatine in Thy-1 Nephritis 2257 model (3,18–20). Therefore, we chose the Thy-1 nephritis showing moderate lucency (25 to 50% disruption of MC) with pres- model to investigate the in vivo effects of agmatine on injury ervation of the underlying glomerular tuft architecture; 3 ϭ MA and repair. showing severe lucency (50 to 75%) with degeneration and disruption ϭ Our results provide the first evidence that agmatine can limit of MC; 4 MA showing complete dissolution (75 to 100%) with MC proliferation and improve renal function in experimental disappearance of MC, usually in association with microaneurysm formation. Matrix score: 0 ϭ decrease in mesangial matrix (MM); 1 mesangial proliferative GN. ϭ no increase in MM; 2 ϭ slight increase in MM; 3 ϭ moderate increase in MM; 4 ϭ almost confluent appearance of MM. Each score Materials and Methods reflects changes in the extent rather than in the intensity of MM Disease Model and Experimental Protocol staining. Proliferation score: 0 ϭ no nests of proliferating cells (PC); Animal experiments were performed using male Sprague-Dawley 1 ϭ normal number of PC; 2 ϭ slight increase in PC; 3 ϭ moderate rats that weighed 200 to 225 g. Rats were allowed free access to increase in PC; 4 ϭ substantial increase in PC. To compare the normal rat chow and tap water. The mouse monoclonal antibody glomerular cell number quantitatively, we individually counted nuclei against rat Thy-1.1 (OX7) was a generous gift from Dr. T. Yamamoto and polymorphonuclear leukocytes (PMN) in 30 glomeruli from each (Niigata University School of Medicine, Japan). This antibody binds rat. to the Thy-1 antigen expressed on the MC membrane and leads to mesangiolysis followed by marked MC proliferation (16,17). The Immunohistochemical Staining for Proliferating Cell animals were divided into three groups. The Thy-1 nephritis group Nuclear Antigen ϭ (Thy-1, n 18) received a single 0.1 ml/kg body wt intravenous Tissue sections in metharcarn solution were incubated overnight at injection of anti–Thy-1 antibody on day 0. The agmatine-treated 4°C with 19A2, a murine IgM monoclonal antibody against human ϩ ϭ Thy-1 nephritis group (Thy-1 Ag, n 18) received a 50 mg/kg body proliferating cell nuclear antigen (PCNA; Coulter cytometry), fol- wt intraperitoneal injection of agmatine (Sigma Chemical Co., St. lowed by a peroxidase-conjugated rat anti-mouse IgM (Zymed Lab- Louis, MO) 2 h before administration of anti–Thy1-antibody and then oratory, San Francisco, CA). PCNA is an acidic nuclear protein that ϭ daily. The agmatine group (Ag, n 18) served as a positive control increases from the late G1 to S phases of the cell cycle, followed by and received the same daily intraperitoneal injections of agmatine as a decrease in G2/M. Black nuclear staining was detected using dia- ϩ the Thy-1 Ag group. Untreated rats were used as a normal control minobenzidine (Dakopatts, Glostrup, Denmark), and slides were ϭ group (Control, n 6). In a separate group of animals, agmatine was counterstained with methyl green. The negative control consisted of administered 24 h after disease induction to confirm that the alter- substitution of the primary antibody with a normal mouse IgM mono- ations in proliferation were not due to agmatine’s ability to limit initial clonal antibody (Dakopatts). To determine the number of proliferating ϭ tissue injury (N 5). At each time point, rats were anesthetized with cells in individual animals, a blinded observer evaluated 30 to 40 sodium brevital (65 mg/kg intraperitoneally) and killed immediately glomerular profiles containing more than 20 discrete capillary seg- after the kidneys were removed at days 0 (Control), 1 (24 h), 4, and ments, and positive staining was defined as black nuclear staining. 7 after anti–Thy-1 antibody injection. The kidneys were immediately fixed for microscopic studies. Kidney cortical slices were obtained for Immunofluorescence Staining for Macrophage/ measurement of ODC activity, and glomeruli isolated from the cortex were used for the cell proliferation, nitrite, and guanosine 3Ј,5Ј-cyclic Monocytes and Anti–Thy-1 Antibody monophosphate (cGMP) assays. To assess whether agmatine reduces anti–Thy-1 antibody binding to glomeruli, thereby causing an alteration in the extent of injury, we performed immunofluorescence studies. Anti–Thy-1 antibody has Awake Animal Studies of GFR and
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