Long‐term evolution of the acute tubular necrosis (ATN) induced by glycerol: role of myofibroblasts and macrophages

Abstract

Summary. Late structural changes such as interstitial fibrosis in the renal cortex and tubular atrophy have been detected after severe acute tubular necrosis (ATN). The aim of this study was to investigate the expression of fibronectin, a-smooth muscle actin and macrophages during the evolution of the ATN induced by glycerol and their relationship with the late structural changes observed in the kidneys of these animals. Forty-nine male Wistar rats were injected with a 50% glycerol solution, 8 mL/kg (4 mL/kg applied i.m. to each hind leg) and 14 with 0.15 M NaCl solution. Before glycerol injection on day 1, water was removed for 17 h. Blood and urine samples were collected 1 day after the injection to quantify sodium and creatinine. The animals were killed 5, 30 and 60 days after the injections and the kidneys removed for histological and immunohistochemical studies. The results of the histological and immunohistochemical studies were scored according to the extent of lesion or staining in the cortical tubulointerstitium, respectively. The percentage of tubulointerstitial lesions was determined by morphometry. Glycerol-injected rats presented a transitory increase in plasma creatinine levels and in fractional sodium excretion. The immunohistochemical studies showed increased fibronectin, a-smooth muscle actin (a-SM-actin), TGF-b and ED-1 (macrophages) staining in the renal cortex from rats killed 5, 30 and 60 days after glycerol injection (P < 0.05) compared to control. The animals killed on day 30 and 60 also presented chronic lesions (fibrosis, tubular dilatation and atrophy) in the renal cortex, despite the recovery of renal function. Macrophages, TGF-b and myofibroblasts may have contributed to the development of renal fibrosis in these rats.

Isolation and Characterization of Multipotent Progenitor Cells from the Bowman’s Capsule of Adult Human Kidneys

“…In our setting, injection of glycerol induced significant increases in serum BUN, which peaked at day 3, declined at day 7, and stabilized at days 11 and 14 to values that were significantly higher than those in healthy mice ( Figure 9, A and B), as described previously (34,35). Intravenous injection of CD24 ϩ CD133 ϩ PEC on days 3…”

Macrophage Depletion Ameliorates Glycerol-Induced Acute Kidney Injury in Mice

“…The proinflammatory response is an important mechanism in the initiation and maintenance of Gly-induced AKI [9,22]. Previous studies reported peak inflammation at 3-5 days after Gly injection [23,24]. In our study, macrophage numbers in kidneys of Gly-treated mice peaked at 24 h. Therefore, early depletion of macrophages by LEC treatment was associated with reduced inflammation in Gly-induced renal injury.…”

Histological Features of Acute Tubular Necrosis in Native Kidneys and Long-Term Renal Function

“…Also in different experimental models, as ischemia, gentamicin, or glycerol, interstitial fibrosis can progress even after functional recovery. [7,14,15] When renal biopsy is performed in native kidney ARF, the histological findings mirror the consequence of an acute injury as tubular necrosis and the response to this acute injury, such as cellular regeneration, inflammatory infiltrate, progressive fibrosis, or loss of glomeruli; however, they also mirror chronic features (present before ARF) such as sclerosed glomeruli and atherosclerotic vascular alterations. Thus, the finding of more intense histological abnormalities in the group with partial recovery represents the result of more severe ARF but also of aging, chronic hypertension, etc.…”

“…[5] Other experimental stud-ies of ARF have also shown that chronic structural changes may be observed after the acute injury. [6,7] In the 1970s, Striker et al pointed to the association between interstitial disease and decline of GFR. [8] A more recent study on ATN after renal transplantation showed that patients who had progressed to chronic renal failure presented larger fractional interstitial area in their biopsies than patients with good outcome (34% versus 19%, p < 0.01).…”