The mechanical disturbance after unilateral ureteral obstruction (UUO) is a nonimmune stimulus that is capable of eliciting a florid macrophage infiltration of the kidney and subsequent post-inflammatory renal scarring. Osteopontin has potential chemoattractant activity and, for this reason, we delineated the kinetics of its expression in the renal cortex of rats with UUO. Whole body X-irradiation and reversal of UUO were utilized as interventional maneuvers to give additional pathobiological insight into this protein's role in the response of the kidneys to ureteral obstruction. Increased osteopontin mRNA levels in obstructed kidneys versus contralateral unobstructed specimens were evident as early as 4 hours after UUO and steadily increased at 12, 24, 48, and 96 hours after UUO. Both X-irradiation and reversal of UUO failed to significantly modulate renal cortical osteopontin mRNA expression at all of the above time points. Paralleling the increments in renal cortical osteopontin mRNA levels were significant elevations in the cortical renal interstitial macrophage number, which was significantly diminished by previous X-irradiation but not reversal of UUO. Focal labeling of osteopontin was noted in both tubular and Bowman's capsular epithelium in obstructed kidneys as early as 4 hours after UUO, whereas, in the contralateral unobstructed specimens, there was only faint staining in Bowman's capsule. By 96 hours after UUO, obstructed kidneys exhibited intense, diffuse staining for osteopontin in both tubules and Bowman's capsule. Osteopontin's immunolocalization was not modulated by X-irradiation or reversal of UUO. These data support the contention that osteopontin is involved in the accumulation of macrophages within the peritubular and periglomerular interstitium in the obstructed renal cortex.

Early cellular and molecular derangements have been evaluated as potential pivotal factors for the late development of interstitial fibrosis after experimental hydronephrosis. In this study, we delineated the kinetics of renal cortical macrophage infiltration as well as the cortical expression of transforming growth factor-beta 1 (TGF-beta 1) and monocyte chemoattractant peptide-1 (MCP-1) at 12, 48, and 96 h after unilateral ureteral obstruction (UUO). Interstitial macrophage number in the obstructed kidney versus the contralateral unobstructed kidney (CUK) significantly increased by 12 (11.1 +/- 0.9 vs. 4.5 +/- 0.6), 48 (27.5 +/- 0.9 vs. 4.0 +/- 0.8), and 96 h (71.4 +/- 4.6 vs. 3.2 +/- 0.4) after UUO. MCP-1 mRNA was detected from 12 to 96 h in the obstructed kidney but was absent in the CUK specimens at all time points. Apical tubular MCP-1 expression, on immunolabeling, was present from 12 through 96 h after UUO in the obstructed kidney but not the CUK specimen. On Northern analysis, there were highly significant 2.6-, 5.8-, and 7.0-fold increments in renal cortical TGF-beta 1 mRNA levels at 12, 48, and 96 h, respectively, in the obstructed kidney versus the CUK specimen. Intracellular TGF-beta 1, on immunolabeling, was detected only in the obstructed kidneys of UUO rats at all three time points and was confined to peritubular cells of the renal interstitium. A significant (P < 0.005) correlation (r = 0.95) between interstitial macrophage number and cortical TGF-beta 1 mRNA levels was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Proteinuria and tubulointerstitial inflammation (TII) correlate with progression to renal failure in human glomerulonephritis. Various forms of experimental nephrotic syndrome are associated with TII. To study the genesis of TII, we utilized the model of albumin overload. Rats received intraperitoneal bovine serum albumin (BSA) for 1 to 14 days, developing heavy proteinuria. A predominantly macrophage interstitial infiltrate was present at days 3, 7 and 14. The urine of the rats contained a factor chemotactic for macrophages which partitioned into the organic phase with ethyl acetate extraction. TLC and HPLC characteristics were those of a novel, non-polar lipid. Supernatant from the culture of proximal tubule (PT) segments after in vivo or in vitro exposure to high concentrations of lipid-replete BSA showed chemotactic activity with similar chromatographic characteristics. PT cultured with delipidated BSA produced little activity. Thus, the generation of this inflammatory factor occurs as a consequence of tubular metabolism of albumin-borne fatty acids and may contribute to the development of proteinuria-associated TII.

In this multimodel overview, we have provided the seminal experimental evidence for the crucial contribution of macrophages in the progression of glomerular and interstitial fibrosis. Although all the experimental data provided in this review definitely increase our understanding of the progress of renal disease, we have been mindful to use caution in extrapolating data from animal experiments to the clinical setting (109). In addition, uncertainty still exists as to whether macrophages activation entails a generalized mechanism in which the cells release growth factors and other mediators such as bioactive lipids and nitric oxide simultaneously, or a selective mechanism in which the cells release some but not all macrophage products (110). However, we anticipate that further substantial clinical and experimental observations are on the horizon. Novel therapeutic strategies in these models must be concerned with the prevention of renal macrophage recruitment and/or the suppression of the fibrogenic ability of this pluripotential inflammatory cell.

Nephrotic syndrome is defined by proteinuria, hypoalbuminemia, edema and hypercholesterolemia. Evidence from both the experimental and clinical literature suggests that high lipid levels are not only a marker of disease, but also contribute to the process of glomerulosclerosis. Lipid mediators, including eicosanoids, platelet-activating factor, and chemotactic factors, can contribute by effecting leukocyte infiltration, mesangial proliferation, extracellular matrix protein production, vasoreactivity, and coagulation. Infiltrating macrophages may play a central role in these processes. Therapeutic maneuvers aimed at the correction of lipid abnormalities may halt or slow the progression of nephrotic syndrome to end-stage renal disease.