Diabetic nephropathy is the leading cause of
end-stage renal disease worldwide, but no effective therapeutic strategy is available. Because
plasminogen activator inhibitor-1 (PAI-1) is increasingly recognized as a key factor in extracellular matrix (ECM) accumulation in
diabetic nephropathy, this study examined the renoprotective effects of
TM5275 and
TM5441, two novel orally active
PAI-1 inhibitors that do not trigger
bleeding episodes, in
streptozotocin (STZ)-induced diabetic mice.
TM5275 (50 mg/kg) and
TM5441 (10 mg/kg) were administered orally for 16 weeks to STZ-induced diabetic and age-matched control mice. Relative to the control mice, the diabetic mice showed significantly increased (p < 0.05) plasma
glucose and
creatinine levels, urinary
albumin excretion, kidney-to-bodyweight ratios, glomerular volume, and fractional mesangial area. Markers of
fibrosis and
inflammation along with
PAI-1 were also upregulated in the kidney of diabetic mice, and treatment with
TM5275 and
TM5441 effectively inhibited
albuminuria, mesangial expansion, ECM accumulation, and macrophage infiltration in diabetic kidneys. Furthermore, in mouse proximal tubular epithelial (mProx24) cells, both
TM5275 and
TM5441 effectively inhibited PAI-1-induced
mRNA expression of
fibrosis and
inflammation markers and also reversed PAI-1-induced inhibition of
plasmin activity, which confirmed the efficacy of the TM compounds as
PAI-1 inhibitors. These data suggest that TM compounds could be used to prevent diabetic kidney injury.