Proteinuria is accompanied by intratubular complement activation and apical membrane deposition of C3dg and C5b-9 in kidney transplant recipients

Autor: Lissel Isaksson, Gustaf, Bodilsen Nielsen, Marie, Hinrichs, Gitte Rye, Krogstrup, Nicoline Valentina, Zachar, Rikke, Stubmark, Heidi, Svenningsen, Per, Madsen, Kirsten, Bistrup, Claus, Jespersen, Bente, Birn, Henrik, Palarasah, Yaseelan, Jensen, Boye L.
Rok vydání: 2022
Předmět:
Zdroj: Lissel Isaksson, G, Bodilsen Nielsen, M, Hinrichs, G R, Krogstrup, N V, Zachar, R, Stubmark, H, Svenningsen, P, Madsen, K, Bistrup, C, Jespersen, B, Birn, H, Palarasah, Y & Jensen, B L 2022, ' Proteinuria is accompanied by intratubular complement activation and apical membrane deposition of C3dg and C5b-9 in kidney transplant recipients ', American Journal of Physiology: Renal Physiology, vol. 322, no. 2, pp. F150-F163 . https://doi.org/10.1152/ajprenal.00300.2021
Isaksson, G L, Bodilsen Nielsen, M, Hinrichs, G R, Krogstrup, N V, Langkilde, R Z, Stubmark, H, Svenningsen, P, Madsen, K, Bistrup, C, Jespersen, B, Birn, H, Palarasah, Y & Jensen, B L 2022, ' Proteinuria is accompanied by intratubular complement activation and apical membrane deposition of C3dg and C5b-9 in kidney transplant recipients ', American Journal of Physiology: Renal Physiology, vol. 322, no. 2, pp. F150-F163 . https://doi.org/10.1152/ajprenal.00300.2021
ISSN: 1522-1466
1931-857X
DOI: 10.1152/ajprenal.00300.2021
Popis: Proteinuria predicts accelerated decline in kidney function in kidney transplant recipients (KTRs). We hypothesized that aberrant filtration of complement factors causes intraluminal activation, apical membrane attack on tubular cells and progressive injury. Biobanked samples from two previous studies in albuminuric KTRs were used. Complement activation split products C3c, C3dg and sC5b-9 associated C9 neoantigen were analyzed by ELISA in urine and plasma using neoepitope-specific antibodies. Urinary extracellular vesicles (uEV) were enriched by lectin- and immunoaffinity-isolation and analyzed by immunoblotting. Urine complement excretion increased significantly in KTRs with albumin/creatinine ratio ≥ 300 mg/g compared to < 30 mg/g. Urine C3dg and C9 neoantigen excretion correlated significantly to changes in albumin excretion from 3 to 12 months after transplantation. The fractional excretion of C9 neoantigen was significantly higher than for albumin indicating post-filtration generation. C9 neoantigen was detected in uEVs in six of nine of albuminuric KTRs but was absent in non-albuminuric controls (n = 8). In C9 neoantigen positive KTRs, lectin-affinity enrichment of uEVs from the proximal tubules yielded signal for iC3b, C3dg, C9 neoantigen and SGLT2 but only weakly for AQP2. Co-isolation of podocyte markers and Tamm-Horsfall protein was minimal. Our findings show that albuminuria is associated with aberrant filtration and intratubular activation of complement with deposition of C3 activation split products and C5b-9 associated C9 neoantigen on uEVs from the proximal tubular apical membrane. Intratubular complement activation may contribute to progressive kidney injury in proteinuric kidney grafts. Proteinuria predicts accelerated decline in kidney function in kidney transplant recipients (KTRs). We hypothesized that aberrant filtration of complement factors causes intraluminal activation, apical membrane attack on tubular cells, and progressive injury. Biobanked samples from two previous studies in albuminuric KTRs were used. The complement-activation split products C3c, C3dg, and soluble C5b-9-associated C9 neoantigen were analyzed by ELISA in urine and plasma using neoepitope-specific antibodies. Urinary extracellular vesicles (uEVs) were enriched by lectin and immunoaffinity isolation and analyzed by immunoblot analysis. Urine complement excretion increased significantly in KTRs with an albumin-to-creatinine ratio of ≥300 mg/g compared with
Databáze: OpenAIRE
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