Plasminogen activator inhibitor-1 in kidney pathology

Abstract

Plasminogen activator inhibitor type-1 (PAI-1) inhibits tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), which convert plasminogen to plasmin, a strong proteolytic enzyme. Thus, PAI-1 is a primary and negative regulator of plasmin-driven proteolysis. In addition to its main role as an inhibitor of fibrinolysis, PAI‑1 has been implicated as a mediator in other processes, including fibrosis, rheumatoid arthritis, atherosclerosis, tumor angiogenesis and bacterial infections. It also significantly modulates cellular adhesion or migration, wound healing, angiogenesis and tumor cell metastasis. However, in the present study, we have reviewed the literature in relation to different kidney diseases where PAI-1 regulates fibrinolysis and acts independently of proteolysis. PAI-1 is normally produced in trace amounts in healthy kidneys but is synthesized in a wide variety of both acute and chronic diseased kidneys. We reviewed the role of PAI-1 in diabetic kidney nephropathy, chronic kidney disease, hemodialysis, peritoneal dialysis and in kidney transplantation. Increased PAI-1 expression results in accumulation of extracellular matrix (ECM) leading to numerous kidney diseases. Predisposition to some diseases is due to the genetic role of PAI-1 in their development. A number of studies demonstrated that the inhibition of PAI-1 activity or therapy with a mutant PAI-1 increases matrix turnover and reduces glomerulosclerosis by competing with endogenous PAI-1. This strongly suggests that PAI-1 is a valid target in the treatment of fibrotic renal disease. However, net proteolytic activity depends on the delicate balance between its negative regulation by PAI-1 and activation by uPA and tPA. Also, plasmin activated by its inhibitors upregulates activity of other enzymes. Thus, assessment of prognosis for the diseased kidney should include a variety of proteolysis regulators and enzymes.

Inhibition of coagulation proteases Xa and IIa decreases ischemia–reperfusion injuries in a preclinical renal transplantation model

“…29 The later observations are strengthened by protein and mRNA expression analyses, as indeed EP reduced the expression of PAI-1 mRNA, a mediator of fibrosis, 30 and metalloproteinase MMP-2 protein, implicated in EMT and fibrosis. 29 There was no difference in TGF- protein expression, possibly due to analysis timing (3 months post-transplantation) in relation to the kinetics of fibrosis development, suggesting that TGF--dependent mechanism of fibrosis initiation could be terminated.…”

4 G/4 G polymorphism ofplasminogen activator inhibitor-1 geneincreases the risk of diabetic nephropathy

“…PAI-1 specifically and swiftly inhibits the activators of plasminogen (tissue urokinase and plasminogen activator), and consequently inhibits fibrinolysis which is associated with thrombosis in DN. 5 Increased PAI-1 expression in DN also leads to the accumulation of extracellular matrix (ECM) which causes kidney disease development. Meanwhile, PAI-1 regulates other cytokines in hemostasis such as tumor necrosis factor a, transforming growth factor b, interleukin 6 and angiotensin II.…”

“…expression in DN. 5 The inhibition of PAI-1 therapy could reduce glomerulosclerosis and increase ECM turnover. 23 Therefore, PAI-1 plays a critical role in the increased risk of DN.…”

“…23 Therefore, PAI-1 plays a critical role in the increased risk of DN. 5 Polymorphisms of the PAI-1 gene could increase the level or activity of PAI-1 in the plasma of humans. The 4 G/5 G variants have been widely studied among all the single nucleotide polymorphisms (SNP) of PAI-1 gene.…”

“…PAI-1 might contribute to the pathogenesis and progression of DN. 5 The PAI-1 gene located at chromosome 7 (q21.3-q22) in human, in which the 4 G/5 G polymorphism (rs1799889) is most studied. A guanosine nucleotide deletion/insertion at À675 bp of the PAI-1 promoter leads to the 4 G/5 G polymorphism which increases PAI-1 expression or activity without changing the t. 6 The association between the risk of DN and the 4 G/5 G variants has been reported by several studies.…”