Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats

被引:145
作者
Kato, S
Luyckx, VA
Ots, M
Lee, KW
Ziai, F
Troy, JL
Brenner, BM
Mackenzie, HS
机构
[1] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Boston, MA USA
关键词
diabetic nephropathy; monocyte transmigration; enalapril; candesartan; proteinuria; macrophage recruitment; glomerular injury;
D O I
10.1046/j.1523-1755.1999.00643.x
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background Glomerular macrophage accumulation in diabetes implicates monocyte recruitment mechanisms in the pathogenesis of diabetic nephropathy. To test the hypothesis that overexpression of monocyte chemoattractant protein-1 (MCP-1), a monocyte chemoattractant, is attenuated by renin-angiotensin system (RAS) inhibition, we assessed expression of genes regulating monocyte transmigration in the glomeruli of diabetic rats. Methods. Competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to semiquantitate mRNA expression in glomeruli harvested by sieving at serial intervals after the induction of diabetes by streptozotocin in Munich-Wistar rats. Although subject to limitations, competitive RT-PCR provides an objective measure suited to the minute quantities of RNA extractable from glomerular isolates. Results. Time-dependent elevation of MCP-1 expression was dramatically suppressed by treatment with the angiotensin-converting enzyme inhibitor enalapril or the AT1 receptor antagonist candesartan, and was closely associated with effects on proteinuria and glomerular macrophage number. By contrast, no sustained suppression of the cell adhesion molecules intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 or the classic MCP-1 stimulators tumor necrosis factor-a or interleukin-lp followed RAS inhibition, and suppression of transforming growth factor-pi expression was transient. Conclusion. These data suggest that glomerular macrophage recruitment in experimental diabetes is largely determined by angiotensin-stimulated MCP-1 expression. We conclude that the RAS is an important regulator of local MCP-1 expression, either directly or through glomerular hemodynamic effects, and that our data strongly implicate macrophage recruitment and activation in the pathogenesis of early diabetic glomerular injury.
引用
收藏
页码:1037 / 1048
页数:12
相关论文
共 60 条
  • [1] SHORT AND LONG-TERM EFFECTS OF ANTIHYPERTENSIVE THERAPY IN THE DIABETIC RAT
    ANDERSON, S
    RENNKE, HG
    GARCIA, DL
    BRENNER, BM
    [J]. KIDNEY INTERNATIONAL, 1989, 36 (04) : 526 - 536
  • [2] Nephron mass modulates the hemodynamic, cellular, and molecular response of the rat renal allograft
    Azuma, H
    Nadeau, K
    Mackenzie, HS
    Brenner, BM
    Tilney, NL
    [J]. TRANSPLANTATION, 1997, 63 (04) : 519 - 528
  • [3] Transforming growth factor-beta in the development of rat diabetic nephropathy - A 10-month study with insulin-treated rats
    Bertoluci, MC
    Schmid, H
    Lachat, JJ
    Coimbra, TM
    [J]. NEPHRON, 1996, 74 (01): : 189 - 196
  • [4] T-CELLS AND MACROPHAGES IN RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS - CLINICOPATHOLOGICAL CORRELATIONS
    BOLTON, WK
    INNES, DJ
    STURGILL, BC
    KAISER, DL
    [J]. KIDNEY INTERNATIONAL, 1987, 32 (06) : 869 - 876
  • [5] BORDER WA, 1995, KIDNEY INT, V47, pS59
  • [6] ISOLATION AND CHARACTERIZATION OF A CDNA CLONE ENCODING FOR RAT CSF-1 GENE - POSTTRANSCRIPTIONAL REPRESSION OCCURS IN MYOGENIC DIFFERENTIATION
    BORYCKI, AG
    LENORMAND, JL
    GUILLIER, M
    LEIBOVITCH, SA
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA, 1993, 1174 (02) : 143 - 152
  • [7] Monocyte chemoattractant protein-1 expression in aortic tissues of hypertensive rats
    Capers, Q
    Alexander, RW
    Lou, PP
    De Leon, H
    Wilcox, JN
    Ishizaka, N
    Howard, AB
    Taylor, WR
    [J]. HYPERTENSION, 1997, 30 (06) : 1397 - 1402
  • [8] CHEHADEH HE, 1995, BIOTECHNIQUES, V18, P26
  • [9] CHOMCZYNSKI P, 1987, ANAL BIOCHEM, V162, P156, DOI 10.1016/0003-2697(87)90021-2
  • [10] KIDNEY-FUNCTION AND SIZE IN DIABETICS BEFORE AND DURING INITIAL INSULIN-TREATMENT
    CHRISTIANSEN, JS
    GAMMELGAARD, J
    TRONIER, B
    SVENDSEN, PA
    PARVING, HH
    [J]. KIDNEY INTERNATIONAL, 1982, 21 (05) : 683 - 688