This study is, to our knowledge, the first to demonstrate that aldosterone regulates PAI-1 expression in vivo, and supports the hypothesis that aldosterone induces renal injury through its effects on PAI-1 expression.

The expression of FGF-1 and FGFR-1 in infiltrating lymphocytes and macrophages, and of FGFR-1 in tubules, is supportive, but does not prove causality, of the possibility that FGF-1 might have both autocrine and paracrine functions in renal inflammation. However, the initial stimulus for renal inflammation, whether immune complex, hypersensitivity or rejection, did not alter expression patterns of FGF-1 or its receptor. The colocalization of inflammatory infiltrates with interstitial fibrosis supports the possibility of a contribution of FGF-1 for chemotaxis and associated fibrosis, further supported by interstitial FSP-1 expression closely associated with these inflammatory cells expressing FGF-1 and FGFR-1.

Protein expression profiles linked to sclerosis in the 5/6 nephrectomy (Nx) rat model of focal segmental glomerulosclerosis were investigated. Sections of control glomeruli from normal baseline Nx tissue and nonsclerotic and sclerotic glomeruli from 12 wk after 5/6 Nx were isolated by laser capture microdissection. Protein profiles were acquired directly by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Classification accuracy was 99.2% for distinguishing normal versus sclerotic glomeruli and 96.7 and 97.8% for nonsclerotic versus normal and sclerotic glomeruli, respectively. The proteomic pattern of the nonsclerotic glomeruli was more similar to sclerotic than normal glomeruli (P < 0.0001). Thymosin ␤4, a protein with relevant interactions with plasminogen activator inhibitor-1, angiogenesis, and wound healing, was identified as a key differentially expressed protein. P rogression of focal segmental glomerulosclerosis (FSGS) from early injury to overt sclerosis involves injury to all glomerular cell types (1,2), through multiple complex mechanisms. With the advancement of proteomic techniques (3,4), simultaneous examination of hundreds of proteins related to kidney disease holds promise in unraveling novel underlying mechanisms of progression and thus identifying possible targets for intervention in FSGS.To obtain protein expression profiles from a localized area, laser capture microdissection (LCM) has been combined with matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) for tissue protein profiling (5,6). LCM is an important tool in biologic research, enabling the isolation of specific cell populations from a heterogeneous tissue section (7). The technique of direct protein profiling from the laser capture microdissected sample using MALDI MS is fast, sensitive, and accurate. This technique has been applied in several studies, including those of human breast carcinoma (5), mouse epididymis (8), and human lung carcinoma (9). This technique enables the determination of protein expression profiles from even minute tissue structures within limited samples.The focal segmental nature of sclerosis in FSGS raises the question of whether at a given time point the remaining nonsclerotic glomeruli are already programmed to sclerotic pathways or, alternatively, whether these remaining nonsclerotic glomeruli have less prosclerotic activation and thus may be more susceptible to therapy. We therefore sought to examine proteomic profiles from the nonsclerotic glomeruli in FSGS and compare profiles from them with normal glomeruli and glomeruli with established sclerosis. We aimed first to establish the sensitivity of LCM and MALDI MS techniques to differentiate sclerosis from normal and, second, to investigate whether nonsclerotic glomeruli have a prosclerotic phenotype at the protein level. We also sought to identify key differentially expressed protein markers to advance our understanding of mechanisms and possible intervention in progressive renal disease. Materials and ...

Our data show that sulodexide can reduce the early, but not late, proteinuria in radiation nephropathy in rats. In addition, sulodexide did not affect urine TGF-beta established albuminuria or mesangial matrix expansion in a chronic model of diabetic kidney disease in mice. Although sulodexide may affect TGF-beta activation in radiation nephropathy, this effect appeared insufficient in this model to inhibit the expressions of PAI-1 and collagen and reduce accumulation of extracellular matrix. These results may explain in part its lack of efficacy in recent clinical trials of chronic kidney disease.

Chronic kidney disease is characterized by progressive glomerulosclerosis and tubulointerstitial fibrosis. High-dose angiotensin type 1 receptor blocker (ARB) or angiotensin-converting enzyme inhibitor can induce regression of existing glomerulosclerosis, at least in part by decreasing matrix accumulation. However, the potential mechanisms of remodeling of capillary loops remain obscure. This study aimed to determine whether capillary branching was augmented in glomeruli with ARB-induced regression of sclerosis. Three-dimensional confocal images were assessed by graph theory analysis to explore the topology of the glomerular capillary network. Compared with normal glomeruli, glomeruli of rats with progressive sclerosis were enlarged but had a significantly reduced number of capillary segments and capillary branch points and decreased complexity of the glomerular network. In contrast, in rats with regression of sclerosis induced by ARB, glomerular enlargement was due to a significantly increased number of glomerular capillary segments and capillary branch points and restored complexity of the capillary network. These data support the theory that capillary growth contributes to regression of sclerosis and is mediated at least in part by ARB-induced increased complexity and branching of capillary segments.