Shiga Toxin 2 Triggers C3a-Dependent Glomerular and Tubular Injury through Mitochondrial Dysfunction in Hemolytic Uremic Syndrome

Abstract

Shiga toxin (Stx)-producing Escherichia coli is the predominant offending agent of post-diarrheal hemolytic uremic syndrome (HUS), a rare disorder of microvascular thrombosis and acute kidney injury possibly leading to long-term renal sequelae. We previously showed that C3a has a critical role in the development of glomerular damage in experimental HUS. Based on the evidence that activation of C3a/C3a receptor (C3aR) signaling induces mitochondrial dysregulation and cell injury, here we investigated whether C3a caused podocyte and tubular injury through induction of mitochondrial dysfunction in a mouse model of HUS. Mice coinjected with Stx2/LPS exhibited glomerular podocyte and tubular C3 deposits and C3aR overexpression associated with cell damage, which were limited by C3aR antagonist treatment. C3a promoted renal injury by affecting mitochondrial wellness as demonstrated by data showing that C3aR blockade reduced mitochondrial ultrastructural abnormalities and preserved mitochondrial mass and energy production. In cultured podocytes and tubular cells, C3a caused altered mitochondrial fragmentation and distribution, and reduced anti-oxidant SOD2 activity. Stx2 potentiated the responsiveness of renal cells to the detrimental effects of C3a through increased C3aR protein expression. These results indicate that C3aR may represent a novel target in Stx-associated HUS for the preservation of renal cell integrity through the maintenance of mitochondrial function.

SARS-CoV-2 spike protein induces lung endothelial cell dysfunction and thrombo-inflammation depending on the C3a/C3a receptor signalling

“…For lung ultrastructural analysis, glutaraldehyde-fixed fragments of lung tissue were processed and examined with a Philips Morgagni 268D transmission electron microscope (Philips, Brno, Czech Republic), as we previously described 54 , 55 .…”

Podocyte injury and death: New insights into lupus nephritis pathogenesis and therapy

“…[25][26][27] In vitro studies have revealed that interactions between C3a and C3aR foster an increase in interleukin (IL)-1β production, which subsequently induces podocyte cytoskeletal rearrangements, while inhibition of C3aR mitigates renal injury. 26,28 This structural and functional sophistication underscores the critical role of podocytes in maintaining the delicate balance of glomerular homeostasis.…”

“…Expression of complement factors, including C1q, C2, C3, C7, and protein S, along with complement receptors, C3aR and C5aR, and complement regulators, such as complement factor H and decay‐accelerating factor, underline the role of podocytes in complement activation 25–27 . In vitro studies have revealed that interactions between C3a and C3aR foster an increase in interleukin (IL)‐1β production, which subsequently induces podocyte cytoskeletal rearrangements, while inhibition of C3aR mitigates renal injury 26,28 . This structural and functional sophistication underscores the critical role of podocytes in maintaining the delicate balance of glomerular homeostasis.…”