A novel mouse model of phospholipase A2 receptor 1-associated membranous nephropathy mimics podocyte injury in patients

The phospholipase A2 receptor 1 (PLA2R1) is the major autoantigen in patients suffering from membranous nephropathy. To date, the lack of endogenous glomerular expression of PLA2R1 in mice and rats has impeded the establishment of PLA2R1-dependent animal models of this disease. Here, we generated a transgenic mouse line expressing murine full-length PLA2R1 in podocytes. Furthermore, expression of murine PLA2R1 did not result in any morphological disturbance as high-resolution confocal microscopy demonstrated an intact nephrin distribution with normal foot processes. Transfer of rabbit anti-mPLA2R1 antibodies to these mice induced nephrotic range proteinuria, hypercholesterolemia, and histomorphological signs of membranous nephropathy. Immunohistochemical and immunofluorescence analyses revealed enhanced staining for murine PLA2R1 in the presence of unaffected staining for murine thrombospondin type-1 domain-containing 7A in the diseased mice, resembling what is classically found in patients with PLA2R1-associated membranous nephropathy Thus, our mouse model of membranous nephropathy will allow investigation of PLA2R1-specific pathomechanisms and may help to develop and assess antigen-specific treatments in vivo. The phospholipase A2 receptor 1 (PLA2R1) is the major autoantigen in patients suffering from membranous nephropathy. To date, the lack of endogenous glomerular expression of PLA2R1 in mice and rats has impeded the establishment of PLA2R1-dependent animal models of this disease. Here, we generated a transgenic mouse line expressing murine full-length PLA2R1 in podocytes. Furthermore, expression of murine PLA2R1 did not result in any morphological disturbance as high-resolution confocal microscopy demonstrated an intact nephrin distribution with normal foot processes. Transfer of rabbit anti-mPLA2R1 antibodies to these mice induced nephrotic range proteinuria, hypercholesterolemia, and histomorphological signs of membranous nephropathy. Immunohistochemical and immunofluorescence analyses revealed enhanced staining for murine PLA2R1 in the presence of unaffected staining for murine thrombospondin type-1 domain-containing 7A in the diseased mice, resembling what is classically found in patients with PLA2R1-associated membranous nephropathy Thus, our mouse model of membranous nephropathy will allow investigation of PLA2R1-specific pathomechanisms and may help to develop and assess antigen-specific treatments in vivo. The pathogenesis of human membranous nephropathy: we are (almost) thereKidney InternationalVol. 97Issue 5PreviewPrimary membranous nephropathy is an autoimmune disease usually associated with antibody to phospholipase A2 receptor (anti-PLA2R). The study by Meyer-Schwesinger et al. describes the first mouse model induced using a PLA2R system to study the pathogenicity of anti-PLA2R. Hyperimmune rabbit anti-PLA2R IgG can induce a primary membranous nephropathy–like glomerulopathy with proteinuria in mice. However, to conclusively establish the pathogenicity of human anti-PLA2R will require additional studies using PLA2R and anti-PLA2R of human origin. Full-Text PDF In This IssueKidney InternationalVol. 97Issue 5PreviewThe pulmonary manifestations of Novel Coronavirus (COVID-19) have been the focus of attention in the pandemic that is upon us. However, other organs may be affected. Cheng et al. from Wuhan, the epicenter of the outbreak, have documented their experience with COVID-19 and the kidney in over 700 patients. Not unexpectedly, many of these patients developed acute kidney injury (AKI), and AKI was associated with a higher risk for in-hospital mortality, as was pre-existing chronic kidney disease. While AKI is not a surprising finding in critically ill patients, the investigators found that upon admission to the hospital for COVID-19 infection, 44% of patients had proteinuria and 27% had hematuria. Full-Text PDF