TEMPORAL DIFFERENCES IN FIBROBLAST PROLIFERATION AND PHENOTYPE EXPRESSION IN RESPONSE TO CHRONIC ADMINISTRATION OF ANGIOTENSIN-II OR ALDOSTERONE

Chronic activation of the circulating renin-angiotensin-aldosterone sy stem (RAAS), as can occur with unilateral renal ischemia (URI), is ass ociated with an adverse structural remodeling of the right and left ve ntricles characterized by reparative (i.e., microscopic scars) and rea ctive (i.e., perivascular/interstitial) fibrosis. The time course and cells involved in fibroplastic and fibrogenic phases of these events a re unclear. Hearts were examined over the course of 8 weeks in rats in fused with either angiotensin II or aldosterone, and compared to rats with URI. Tissue sections from the same heart were stained with hemato xylin and eosin, collagen specific picrosirius red, or immunolabeled w ith PCNA or alpha smooth muscle actin antibody. With angiotensin II or renal ischemia, fibroblast proliferation presenting as focal accumula tions at both sites of myocyte necrosis and widespread perivascular lo cations, was present in each ventricle on days 2 and 4, but not therea fter. alpha-Smooth muscle actin containing cells (myofibroblasts) appe ared at day 2 and persisted through week 2 with renal ischemia and wee k 6 with angiotensin II. Macrophages, neutrophils and lymphocytes were transiently found at sites of necrosis between day 2-4 of renal ische mia. AgII-induced necrotic sites were characterized by macrophages and lymphocytes from day 2 through week 6, and neutrophils at day 2-4. In creased collagen volume fraction, presenting as immature scars associa ted with fibroblast clusters and interstitial/perivascular fibrosis, w as evident on day 14 in both ventricles. In contrast, fibroblast proli feration during aldosterone infusion did not appear in both Ventricles until week 3 and was associated with a subsequent reparative and reac tive fibrosis as early as 4 weeks, Myofibroblasts became evident betwe en 3-6 weeks; macrophages and lymphocytes were seen between 3-8 weeks. Neutrophils were not seen at any time point with aldosterone. Thus, t he temporal cellular response and appearance of myocardial fibrosis as sociated with chronic elevations in angiotensin II and/or aldosterone differ. We conclude that separate pathogenic mechanisms are operative with these effector hormones of the RAAS. (C) 1995 Academic Press Limi ted.