Local actions of endogenous angiotensin II in injured glomeruli.

Ma J, Matsusaka T, Yang H, Kawachi H, Shimizu F, Isaka Y, Imai E, Kon V, Ichikawa I
J Am Soc Nephrol. 2004 15 (5): 1268-76

PMID: 15100367 · DOI:10.1097/01.asn.0000125675.70674.0f

A previous study showed that exogenous angiotensin II (AngII) induces proliferation of glomerular cells through systemic actions of AngII. In the present study, the authors examined the mode of actions of endogenous AngII in injured kidneys that were made deficient in AT1 by using in vivo transfection of antisense oligodeoxynucleotide (AS-ODN). Thy-1 nephritis was induced in rats by injection of mAb 1-22-3. Four days later, glomerular transfection was performed by unilateral whole-kidney electroporation after AT1 AS-ODN delivery through the left renal artery (n = 7). The expression of renal AT1 was assessed by autoradiography. The effect of the AS-ODN transfection was assessed 3 d later and compared with transfection with control ODN (n = 6), systemically administered pharmacologic AT1 antagonist losartan (n = 5) as well as untreated Thy-1 animals (n = 5). Fluorescence-labeled AS-ODN was found transfected in almost all glomeruli and localized primarily to the mesangium. Compared with the contralateral untransfected kidney in both normal and Thy-1 rats, AS-ODN suppressed cortical AT1 expression by some 70%. The AS-ODN transfected kidneys of Thy-1 rats had significantly lower glomerular mesangial cell proliferation (7.38 +/- 0.68 cells/glomerulus) and extracellular matrix accumulation (0.262 +/- 0.009) than kidneys transfected with control ODN (10.94 +/- 0.51 cells/glomerulus and 0.342 +/- 0.031), contralateral untransfected kidneys (9.56 +/- 1.01 cells/glomerulus and 0.371 +/- 0.011), or kidneys that were exposed to Thy-1 alone (10.45 +/- 1.06 cells/glomerulus and 0.359 +/- 0.013). There were no significant differences in systolic BP among groups. In glomeruli, immunohistochemistry detected no difference in AT2 receptor expression, number of ED1-positive macrophages or number of apoptotic cells among groups. Thus, in renal injury induced by Thy-1 nephritis, selective suppression of mesangial AT1 expression by AS-ODN significantly reduced mesangial cell proliferation and matrix. These data provide in vivo evidence that injured glomeruli are sensitive to local tissue actions of AngII, which promote proliferation and matrix accumulation within the glomerulus.

MeSH Terms (18)

Angiotensin II Angiotensin II Type 1 Receptor Blockers Animals Antihypertensive Agents Cell Division DNA, Antisense Genetic Therapy Glomerular Mesangium Glomerulonephritis Isoantibodies Kidney Glomerulus Losartan Male Rats Rats, Wistar Receptor, Angiotensin, Type 1 Receptor, Angiotensin, Type 2 Transfection

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