Local proximal tubule complement contributes to maladaptive repair in rhabdomyolysis-induced acute kidney injury and escapes systemic inhibition
Abstract
Background and hypothesis : Maladaptive repair drives progression from acute kidney injury (AKI) to chronic kidney disease. Injured proximal tubular cells overexpress complement C3 mRNA, but its functional role is not well understood. We hypothesized that complement proteins produced and active locally within proximal tubules drive maladaptive repair and remain inaccessible to plasma-targeted inhibitors. Methods : We investigated complement, encompassing extracellular, autocrine and intracellular pools, in human biopsies and mouse model of rhabdomyolysis-induced AKI (RIAKI). Hyperplex sequential immunofluorescence combined with RNAscope was used to localize complement proteins and transcripts in situ and immune infiltrate. C3 or factor B (FB) deficient mice and pharmacological FB inhibition were tested in a RIAKI model. Bulk transcriptomics and C3/CFB knockdown in tubular cells with rescue experiments dissected mechanisms in vivo and in vitro . Results : In human and experimental RIAKI, injured VCAM-1 proximal tubules showed reabsorption and local transcription of C3 and CFB in a subset of tubules, induced by inflammatory cytokines. Genetic deletion of C3 or Cfb attenuated AKI, reducing tubular necrosis, immune infiltration and signatures of epithelial-to-mesenchymal transition and maladaptive repair. Pharmacological FB inhibition reduced extracellular C3 activation but did not preserve renal function. In vitro , C3 or FB knockdown in tubular cells suppressed proliferation, inflammation and mTOR-linked metabolic pathways and was not rescued by exogenous purified protein, consistent with cell-intrinsic/intracellular mode of action. Conclusion : Locally produced complement in proximal tubules drives inflammatory and maladaptive repair programs during AKI. The dissociation between genetic deletion and pharmacological FB inhibition indicates that the relevant complement activity occurs in a compartment poorly accessible to systemic inhibitors and supports development of locally acting, tissue-penetrant or cell-permeable complement-targeted therapies for AKI.
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BibTeX
@misc{grunenwald2026local,
title = {{Local proximal tubule complement contributes to maladaptive repair in rhabdomyolysis-induced acute kidney injury and escapes systemic inhibition}},
author = {Anne Grunenwald and Idris Boudhabhay and Margot Revel and Victoria Poillerat and Mikel Rezola Artero and Sara Soares Tozoni and Alaeddine Redissi and Elodie Voilin and Emma Fleury and Julie Peliconi and Alessandra Zarantonello and Gilles Crambert and Andrea Novais Moreno Amaral and Steven Sacks and Viviane Gnemmi and Marie Frimat and Jean-Paul Duong-Van-Huyen and Nicolas S Merle and Lubka Roumenina},
howpublished = {HAL},
year = {2026},
month = jun,
doi = {10.21203/rs.3.rs-9932397/v1},
url = {https://hal.sorbonne-universite.fr/hal-05781758v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Local proximal tubule complement contributes to maladaptive repair in rhabdomyolysis-induced acute kidney injury and escapes systemic inhibition
AU - Anne Grunenwald
AU - Idris Boudhabhay
AU - Margot Revel
AU - Victoria Poillerat
AU - Mikel Rezola Artero
AU - Sara Soares Tozoni
AU - Alaeddine Redissi
AU - Elodie Voilin
AU - Emma Fleury
AU - Julie Peliconi
AU - Alessandra Zarantonello
AU - Gilles Crambert
AU - Andrea Novais Moreno Amaral
AU - Steven Sacks
AU - Viviane Gnemmi
AU - Marie Frimat
AU - Jean-Paul Duong-Van-Huyen
AU - Nicolas S Merle
AU - Lubka Roumenina
PY - 2026
DA - 2026/06/11
PB - HAL
DO - 10.21203/rs.3.rs-9932397/v1
UR - https://hal.sorbonne-universite.fr/hal-05781758v1
AB - Background and hypothesis : Maladaptive repair drives progression from acute kidney injury (AKI) to chronic kidney disease. Injured proximal tubular cells overexpress complement C3 mRNA, but its functional role is not well understood. We hypothesized that complement proteins produced and active locally within proximal tubules drive maladaptive repair and remain inaccessible to plasma-targeted inhibitors. Methods : We investigated complement, encompassing extracellular, autocrine and intracellular pools, in human biopsies and mouse model of rhabdomyolysis-induced AKI (RIAKI). Hyperplex sequential immunofluorescence combined with RNAscope was used to localize complement proteins and transcripts in situ and immune infiltrate. C3 or factor B (FB) deficient mice and pharmacological FB inhibition were tested in a RIAKI model. Bulk transcriptomics and C3/CFB knockdown in tubular cells with rescue experiments dissected mechanisms in vivo and in vitro . Results : In human and experimental RIAKI, injured VCAM-1 proximal tubules showed reabsorption and local transcription of C3 and CFB in a subset of tubules, induced by inflammatory cytokines. Genetic deletion of C3 or Cfb attenuated AKI, reducing tubular necrosis, immune infiltration and signatures of epithelial-to-mesenchymal transition and maladaptive repair. Pharmacological FB inhibition reduced extracellular C3 activation but did not preserve renal function. In vitro , C3 or FB knockdown in tubular cells suppressed proliferation, inflammation and mTOR-linked metabolic pathways and was not rescued by exogenous purified protein, consistent with cell-intrinsic/intracellular mode of action. Conclusion : Locally produced complement in proximal tubules drives inflammatory and maladaptive repair programs during AKI. The dissociation between genetic deletion and pharmacological FB inhibition indicates that the relevant complement activity occurs in a compartment poorly accessible to systemic inhibitors and supports development of locally acting, tissue-penetrant or cell-permeable complement-targeted therapies for AKI.
ER -