Add-On Cyclic Angiotensin-(1-7) with Cyclophosphamide Arrests Progressive Kidney Disease in Rats with ANCA Associated Glomerulonephritis

Abstract

Rapidly progressive crescentic glomerulonephritis associated with anti-neutrophil cytoplasmic antibodies (ANCA-GN) is a major cause of renal failure. Current immunosuppressive therapies are associated with severe side effects, intensifying the need for new therapeutic strategies. The activation of Mas receptor/Angiotensin-(1-7) axis exerted renoprotection in chronic kidney disease. Here, we investigated the effect of adding the lanthionine-stabilized cyclic form of angiotensin-1-7 [cAng-(1-7)] to cyclophosphamide in a rat model of ANCA-GN. At the onset of proteinuria, Wistar Kyoto rats with ANCA-GN received vehicle or a single bolus of cyclophosphamide, with or without daily cAng-(1-7). Treatment with cAng-(1-7) plus cyclophosphamide reduced proteinuria by 85% vs. vehicle, and by 60% vs. cyclophosphamide, and dramatically limited glomerular crescents to less than 10%. The addition of cAng-(1-7) to cyclophosphamide protected against glomerular inflammation and endothelial rarefaction and restored the normal distribution of parietal epithelial cells. Ultrastructural analysis revealed a preserved GBM, glomerular endothelium and podocyte structure, demonstrating that combination therapy provided an additional layer of renoprotection. This study demonstrates that adding cAng-(1-7) to a partially effective dose of cyclophosphamide arrests the progression of renal disease in rats with ANCA-GN, suggesting that cAng-(1-7) could be a novel clinical approach for sparing immunosuppressants.

Antiglomerular basement membrane antibody type rapidly progressive glomerulonephritis with seizures: Two cases and literature review

“…RPGN is clinically manifestations as a rapidly progressive renal failure and pathologically as crescentic and necrotizing lesions with infiltration of inflammatory cells in the glomeruli 14 . The autoimmune development of antibodies towards type IV collagen in the glomerular and alveolar basement membranes leads to patients typically presenting with RPGN and pulmonary hemorrhage 15–17 . Evidence of anti‐GBM antibodies in serum or histologically is required for diagnosis 18 .…”

“…14 The autoimmune development of antibodies towards type IV collagen in the glomerular and alveolar basement membranes leads to patients typically presenting with RPGN and pulmonary hemorrhage. 15 , 16 , 17 Evidence of anti‐GBM antibodies in serum or histologically is required for diagnosis. 18 Treatment mainly involves the use of apheresis and intensive, strong immunosuppression such as cyclophosphamide.…”

Animal models for anti‐neutrophil cytoplasmic antibody‐associated vasculitis: Are current models good enough?

“…Another paper published at the same time also showed that the coadministration of a low dose of nephrotoxic anti‐rat GBM serum enables this model to resemble the characteristic features of disease in humans 27 . Recently, the enhanced EAV rat model induced by human MPO and anti‐rat GBM serum has been put into use in a pre‐clinical therapeutic approach assessment 28 …”

“… 27 Recently, the enhanced EAV rat model induced by human MPO and anti‐rat GBM serum has been put into use in a pre‐clinical therapeutic approach assessment. 28 …”