Long-chain polyphosphates induce glomerular microthrombi and exacerbate LPS-induced acute kidney injury in mouse

Polyphosphates (PolyPs) are evolutionarily conserved anionic polymers mediating pleiotropic functions in eukaryotes and prokaryotes, depending on their chain length. Bacteria typically synthetize long chains, while human platelets harbor exclusively medium chains. PolyP-mediated lung and liver-injury have been reported in experimental mouse models but their effects on the kidney remain undefined. Here, we assessed kidney histopathology and cytokine levels following intravenous administration of medium-chain (P100) and long-chain (P700) PolyPs and their synergistic effects with lipopolysaccharides (LPS) in mice. We found that P700 induced albuminuria, renal transcription of Kim-1 and Lcn2, focal renal damage with glomerular microthrombi, tubular degeneration, granular phenotype of slit diaphragm components nephrin and ZO1 (also known as TJP1), and enlarged electron-dense vesicles in podocyte cytoplasm indicating lysosome swelling. P700 combined with LPS induced marked multifocal acute tubular necrosis in the cortex and augmented LPS-induced pro-inflammatory cytokine levels. No notable effects were seen with P100, indicating that development of PolyP-mediated kidney injury is dependent on chain length. We conclude that P700 PolyPs may play a procoagulant role in kidney injury development, by inducing microthrombi characteristic of thrombotic microangiopathy and augmenting cytokine levels under inflammatory conditions.