Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease: Evidence and Mechanisms of Action Allison A. Eddy* and Agnes B. Fogo† *Children’s Hospital and Regional Medical Center, Department of Pediatrics, University of Washington, Seattle, Washington; and †Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee J Am Soc Nephrol 17: 2999–3012, 2006. doi: 10.1681/ASN.2006050503 n 1984, Loskutoff et al. (1) purified plasminogen activator PAI-1 Is Present in Most Aggressive Kidney inhibitor-1 (PAI-1) from conditioned media of cultured Diseases I endothelial cells. This 50-kd glycoprotein is the primary Acute/Thrombotic Diseases physiologic inhibitor of the serine proteases tissue-type and Thrombotic microangiopathy (TMA) is a pathologic lesion urokinase-type plasminogen activators (tPA and uPA, respec- that is characterized by fibrin deposition in the microvascula- tively). It now is known to mediate important biologic activities ture, often involving glomeruli and renal arterioles. TMA char- that extend far beyond fibrinolysis through interactions with its acterizes renal diseases that are caused by hemolytic uremic co-factor, vitronectin (also known as protein S), and with the syndrome, preeclampsia, scleroderma, malignant hyperten- urokinase receptor (uPAR) and its co-receptors (2,3). Plasma sion, and the antiphospholipid antibody syndrome. Glomerular PAI-1 levels increase in response to stress as an acute-phase PAI-1 deposition is a feature of TMA (10). In children who have protein. Usually present in trace amounts, plasma PAI-1 levels Escherichia coli 0157:H7 infection and later develop hemolytic uremic syndrome (11), plasma PAI-1 levels increase before the increase in several chronic inflammatory states that are associ- onset of renal disease. Plasma PAI-1 activity correlates with ated with chronic kidney disease (CKD), and it may contribute renal disease severity and long-term outcome (12–15). One to the pathogenesis of the accelerated vascular disease in this pediatric study found that PAI-1 activity also increases during patient population (4–7). Liver and adipose tissue seem to be acute renal failure of other causes (16). Animal hemolytic ure- the primary sources of plasma PAI-1 (8,9). Other inhibitors of mic syndrome models that should provide specific insights into plasminogen activation exist; protease nexin-1 and ␣-2 anti- the pathogenetic role of PAI-1 are under development (17,18). plasmin can be produced by the kidney. The extent to which renal PAI-1 is produced locally or derived Although PAI-1 normally is not produced in kidneys, syn- from the plasma pool has not been determined. thesis by both resident and intrarenal inflammatory cells occurs PAI-1 expression is a feature of preeclampsia (19) and sclero- in several acute and chronic disease states (Table 1). In the past derma, although experimental data suggest that PAI-1 is not decade, a growing body of experimental evidence that has essential in the latter (20,21). Radiation nephropathy is charac- derived largely from animal models supports the view that terized in its early phase by TMA with PAI-1 generation, and it PAI-1 is a powerful fibrosis-promoting molecule and is a prom- often progresses to sclerosis. Angiotensin or aldosterone inhi- ising therapeutic target for new drugs and biologics to combat bition reduces PAI-1 levels and the severity of glomerular the current CKD epidemic (Table 2). Exactly how PAI-1 pro- sclerosis in experimental radiation nephropathy (22,23). motes renal fibrosis is not understood completely. Recent stud- ies suggest that in addition to its ability to inhibit serine pro- Crescentic Glomerulonephritis tease activity within vascular and extracellular compartments, Crescents develop as a result of segmental breaks of the PAI-1 directly modulates cellular behavior, leading to a vicious glomerular basement membrane (GBM), often in association cycle of inflammatory cell recruitment, fibroblast activation, with fibrinoid necrosis. In human crescentic glomerulonephri- and scar tissue accumulation. tis, PAI-1 is detected both in areas of glomerular necrosis and in crescents (24,25). Parietal epithelial cells are a source of PAI-1 and uPA in human crescentic glomerulonephritis (26). In experimental models of anti-GBM crescentic nephritis, PAI-1 is produced, whereas tPA levels are suppressed, leading Published online ahead of print. Publication date available at www.jasn.org. to decreased net glomerular fibrinolytic activity and prolonged Address correspondence to: Dr. Allison Eddy, Children’s Hospital and Regional fibrin deposition (27). A functional role for PAI-1 in the patho- Medical Center, Division of Nephrology, Mail Stop M1-5, 4800 Sand Point Way NE, Seattle, WA 98105. Phone: 206-987-2524; Fax: 206-987-2636; E-mail: genesis of anti-GBM crescentic glomerulonephritis was estab- [email protected] lished by elegant studies in genetically engineered mice (Table Copyright © 2006 by the American Society of Nephrology ISSN: 1046-6673/1711-2999 3000 Journal of the American Society of Nephrology J Am Soc Nephrol 17: 2999–3012, 2006 Table 1. Human diseases with intrarenal PAI-1 trix accumulation (36). PAI-1 inhibition by a mutant PAI-1 that expressiona binds matrix vitronectin but does not inhibit plasminogen ac- tivator results in significant reduction in extracellular matrix Diabetic nephropathy (41,146) (ECM) accumulation (37). This treatment also was linked to Focal necrotizing glomerulonephritis (32) increased glomerular plasmin activity and enhanced ECM deg- Crescentic glomerulonephritis (24–26) radation. However, mRNA levels for genes encoding ECM Focal segmental glomerulosclerosis (32,147) proteins also were decreased, perhaps as a consequence of Membranous nephropathy (32,148) decreased macrophage infiltration and plasmin-independent Chronic allograft nephropathy (124,149,150) effects. Thrombotic microangiopathy (10,24) Arterionephrosclerosis (41,151) PAI-1 in Chronic Progressive Renal Disease aPAI-1, plasminogen activator inhibitor-1. In addition to its effects on fibrinolysis that may promote thrombotic and necrotizing renal lesions, PAI-1 has complex interactions with matrix proteins that enhance matrix accumu- 2) (28). The PAI-1Ϫ/Ϫ mice developed fewer glomerular cres- lation in several glomerular disease states (38–40). In humans, cents and glomerular fibrin deposits and reduced collagen ac- PAI-1 is prominent in atherosclerotic lesions and in sclerotic cumulation long term. In contrast, mice that were engineered to glomeruli that are damaged as a consequence of hypertensive overexpress PAI-1 formed more crescents along with more nephrosclerosis, diabetic nephropathy, and chronic allograft extensive fibrin deposits and extensive collagen accumulation. nephropathy. Plasma PAI-1 levels are increased in patients Genetic manipulations that reduce serine protease activity, ei- with insulin resistance and obesity as well as overt diabetes ther plasminogen deficiency or combined uPA and tPA defi- (38–40). Within the kidney, PAI-1 protein is prominent in ciency, also lead to aggressive injury with more extensive cres- Kimmelstiel-Wilson nodules, often associated with fragmented cents, necrosis, and fibrin deposition (29). Isolated tPA red blood cells in regions of local injury and mesangiolysis (41). deficiency causes glomerular injury that is intermediate be- Because adipose tissue is an important source of PAI-1, it also tween wild-type and combination PA knockout mice, whereas may be important in the genesis of the nephropathy of obesity isolated uPA deficiency results in fewer glomerular macro- that may develop even in the absence of diabetes (42). phages, but, otherwise, disease severity is similar to the wild- Although rodent models of diabetes do not develop robust type mice, suggesting that tPA is the primary glomerular plas- glomerular sclerosis or interstitial fibrosis, there is evidence to minogen activator. A different outcome was observed in a support a role for PAI-1 in the pathogenesis of diabetic ne- passive model of anti-GBM glomerulonephritis, in which PAI- phropathy. In the mouse model of mild diabetic injury that is 1Ϫ/Ϫ mice developed more severe renal injury that was attrib- induced by streptozotocin injection, PAI-1Ϫ/Ϫ mice have re- uted to plasminogen activator–dependent activation of TGF-␤ duced albuminuria and fibronectin levels compared with wild- (30). It was postulated further that enhanced TGF-␤ activity type diabetic mice (43). In the db/db mouse model, PAI-1 defi- ϩ influenced CD4 T cell responses, leading to disease exacerba- ciency also was associated with reduced albuminuria and tion. It is possible that differences in the mouse strain may kidney collagen levels, but a high mortality rate was observed account for some of these divergent observations in the genet- (44). In early streptozotocin-induced nephropathy in rats, spi- ically engineered mouse studies. It is remarkable, however, that ronolactone therapy reduced PAI-1 and TGF-␤ expression lev- whenever renal plasmin activity is measured in these mice, it is els and matrix deposition (45). In another study, PAI-1Ϫ/Ϫ not found to differ significantly from that of wild-type mice. mice failed to develop the diabetic phenotype that was induced in wild-type mice by feeding a high-fat diet (46). Furthermore, Proliferative Glomerulonephritis PAI-1Ϫ/Ϫ adipocytes were functionally distinct. They pro- PAI-1 mRNA and protein are increased in both human and duced lower levels of several hormones that have