Plasminogenuria is associated with podocyte injury, edema, and kidney dysfunction in incident glomerular disease

Abstract

Urinary plasminogen/plasmin, or plasmin(ogen)uria, has been demonstrated in proteinuric patients and exposure of cultured podocytes to plasminogen results in injury via oxidative stress pathways. A causative role for plasmin(ogen) as a “second hit” in kidney disease progression has yet to be demonstrated in vivo, and the association between plasmin(ogen)uria and kidney function in glomerular diseases remains unclear. We performed comparative studies in a puromycin aminonucleoside (PAN) nephropathy rat model treated with amiloride, an inhibitor of plasminogen activation, and measured changes in plasmin(ogen)uria and urinary endothelin-1 (ET1). In a glomerular disease biorepository cohort (n=128), we measured time-of- biopsy albuminuria, proteinuria, and plasmin(ogen)uria for correlations with renal outcomes. Increased glomerular plasmin(ogen) was found in PAN rats and FSGS patients. PAN nephropathy was associated with increases in plasmin(ogen)uria, proteinuria, and urinary ET1. Amiloride was protective against PAN- induced glomerular injury, reducing urinary ET1 and oxidative stress. In patients, we found associations between plasmin(ogen)uria and edema status as well as eGFR. Our study demonstrates a role for plasmin(ogen)-induced podocyte injury in the PAN nephropathy model, with amiloride having podocyte- protective properties. In one of largest glomerular disease cohorts to study plasminogen, we validated previous findings while suggesting a potentially novel relationship between plasmin(ogen)uria and eGFR. Together, these findings suggest a role for plasmin(ogen) in mediating glomerular injury and as a viable targetable biomarker for podocyte-sparing treatments.

Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis

“…In C-PROBE, participants were enrolled between 2009 and 2016. Full details of these cohorts were previously published (39,40). For validation cohorts, we defined the presence or absence of AIN based on official biopsy interpretations.…”

Sulfuretted hydrogen ameliorates high dose glucose-induced podocyte apoptosis via orchestrating AMPK/mTOR cascade-mediated anti-apoptotic effects

“…Podocytes play a pivotal role in the maintenance of the glomerular filtration barrier, whereas podocyte injury usually results in proteinuria and detachment from the human glomerular basement membrane (3,4). Current studies Original Article on the biology and gene disruption of podocytes have indicated the causal relationship between abnormalities of podocytes and proteinuria and glomerulosclerosis (4)(5)(6). Over the decades, a number of glomerular responses to podocyte dysfunction have been determined, which has helped to decode the complex scenario of podocyte injury and the resultant consequences.…”

“…Meanwhile, we and other investigators have explored potential therapeutics for podocyte injury and the underlying molecular mechanisms (1,7,8). For example, Egerman and colleagues recently verified the role of plasmin-induced podocyte injury in the puromycin aminonucleoside (PAN) nephropathy model, and have demonstrated that amiloride also has podocyteprotective properties (5). Chen et al verified that hydrogen sulfide (H 2 S) confers a protective effect against TNFα-induced neuronal cell apoptosis via miR-485-5p and type 1-associated DEATH domain protein (TRADD) signaling (9).…”