Nephritis-Associated Plasmin Receptor (NAPlr): An Essential Inducer of C3-Dominant Glomerular Injury and a Potential Key Diagnostic Biomarker of Infection-Related Glomerulonephritis (IRGN)

Abstract

Nephritis-associated plasmin receptor (NAPlr) was originally isolated from the cytoplasmic fraction of group A Streptococci, and was found to be the same molecule as streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and plasmin receptor (Plr) on the basis of nucleotide and amino acid sequence homology. Its main functions include GAPDH activity, plasmin-binding capacity, and direct activation of the complement alternative pathway (A-P). Plasmin trapped by deposited NAPlr triggers the degradation of extracellular matrix proteins, such as glomerular basement membranes and mesangial matrix, and the accumulation of macrophages and neutrophils, leading to the induction of plasmin-related endocapillary glomerular inflammation. Deposited NAPlr at glomerular endocapillary site directly activates the complement A-P, and the endocapillary release of complement-related anaphylatoxins, C3a and C5a, amplify the in situ endocapillary glomerular inflammation. Subsequently, circulating and in situ-formed immune complexes participate in the glomerular injury resulting in NAPlr-mediated glomerulonephritis. The disease framework of infection-related glomerulonephritis (IRGN) has been further expanded. GAPDH of various bacteria other than Streptococci have been found to react with anti-NAPlr antibodies and to possess plasmin-binding activities, allowing glomerular NAPlr and plasmin activity to be utilized as key biomarkers of IRGN.

Proliferative glomerulonephritis with monoclonal immunoglobulin G3 lambda deposits accompanied by glomerular positive staining for nephritis-associated plasmin receptor and related plasmin activity: A report of two cases

“…Indeed, various forms of glomerulonephritis with positive staining for NAPlr and plasmin activity have recently been reported, even if the causative pathogens of infection could not be identified (9,14,15). The specificity of anti-NAPlr antibody for bacterial GAPDH has also been confirmed by Western blotting (12). Furthermore, as far as we know, positive staining for NAPlr has been reported only in glomerular lesions with endocapillary proliferation, with distinct C3 deposition, and with EDD.…”

“…NAPlr and related plasmin activity are assumed to be involved in the development of glomerular lesions, especially at the initial phase. Indeed, glomerular positive staining for NAPlr and plasmin activity was frequently observed in the early-phase PSAGN patients and was initially considered as specific histological markers for PSAGN, although these markers usually disappear at the later phase ( 12 ). They reportedly disappear within 30 days after the disease onset in patients with PSAGN, and therefore it could be possible that NAPlr and plasmin activity were not observed in glomerular lesions, if the renal biopsy was not performed during the acute phase.…”

The Impact of Infections on the Progression of Chronic Kidney Disease

“…Also, a series of biomarkers have been proposed to help in recognizing which patients should be monitored more closely because of an increased risk for progression, like nephritis-associated plasmin receptor and interstitial alfa-smooth muscle actin [11]. The first was initially isolated from group A streptococci and it is involved in maintaining glomerular inflammation through local activation of the complement system, and the second is a marker of tubulointerstitial fibrosis [11,12]. In addition, regarding urinary tract infections, a key element in pathophysiology that predisposes the patients to this type of infection is represented by genetic polymorphisms of Toll-like receptors (TLRs) [13,14].…”

Infection-Related Cryoglobulinemic Glomerulonephritis with Serum Anti-Factor B Antibodies Identified and Staining for NAPlr/Plasmin Activity Due to Infective Endocarditis

“…NAPlr is the same molecule as streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and serves as a histological marker of IRGN, as its presence strongly suggests a prior or ongoing infection. Glomerular positive staining for NAPlr and plasmin activity have been reported in many cases of IRGN [3]. Serum anti-FB antibodies, which activate alternative pathways during infections, are particularly useful for diagnosing IRGN in cases of GN with low serum C3 [4].…”