Angiogenin Mediates Cell-Autonomous Translational Control under Endoplasmic Reticulum Stress and Attenuates Kidney Injury

Abstract

Endoplasmic reticulum (ER) stress is involved in the pathophysiology of kidney disease and aging, but the molecular bases underlying the biologic outcomes on the evolution of renal disease remain mostly unknown. Angiogenin (ANG) is a ribonuclease that promotes cellular adaptation under stress but its contribution to ER stress signaling remains elusive. In this study, we investigated the ANG-mediated contribution to the signaling and biologic outcomes of ER stress in kidney injury. ANG expression was significantly higher in samples from injured human kidneys than in samples from normal human kidneys, and in mouse and rat kidneys, ANG expression was specifically induced under ER stress. In human renal epithelial cells, ER stress induced ANG expression in a manner dependent on the activity of transcription factor XBP1, and ANG promoted cellular adaptation to ER stress through induction of stress granules and inhibition of translation. Moreover, the severity of renal lesions induced by ER stress was dramatically greater in ANG knockout mice (Ang 2/2 ) mice than in wild-type mice. These results indicate that ANG is a critical mediator of tissue adaptation to kidney injury and reveal a physiologically relevant ER stressmediated adaptive translational control mechanism.

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

“…MANF localizes in the ER lumen and is secreted in response to ER stress in several cell types. Similarly, angiogenin was identified as an ER stress responsive biomarker found in the urine of patients with kidney damage . Thus, noninvasive ER stress‐related biomarkers can be used to stratify disease risk and disease development (Fig.…”

Chromatolysis: Do injured axons regenerate poorly when ribonucleases attack rough endoplasmic reticulum, ribosomes and RNA?

“…Where might these ribonucleases come from? There is one report that chromatolysis can be prevented by protein synthesis inhibitors (Torvik and Heding, ) indicating that chromatolysis may be due to a newly‐synthesized enzyme (Bates et al, ; Mami et al, ). Alternatively, perhaps ribonucleases that are associated with ribosomes (Datta and Ghosh, ; Bransgrove and Cosquer, ; Bates et al, ; Bates et al, ; Schoenberg and Maquat, ) become activated after injury (Allam et al, ).…”

“…ER stress can induce autophagy in other cell types and it is possible that axonal or somatic ER stress is the initiator of chromatolysis (Ying et al, ). For example, activation of the IRE1α‐XBP pathway indirectly leads to synthesis of Ribonuclease 5 [after kidney injury; (Mami et al, )]. Moreover, IRE1α is a ribonuclease that is known to degrade a wide range of mRNAs in the ER in a process known as RIDD [regulated IRE1α‐dependent decay; (Li et al, )].…”

Endoplasmic reticulum stress and kidney dysfunction

“…Angiogenin is a secreted ribonuclease expressed under the control of sXBP1 that dissociates from its inhibitor RNH1 under ER stress and affords cytoprotection in reducing protein synthesis through stress‐induced transfer RNA fragments (tiRNA)‐mediated translation initiation repression. Consistently, ER‐stress‐induced AKI in Ang −/− mice is more severe compared to that of their wild‐type counterparts [Mami et al., ]. Supporting the protective effects of the UPR in AKI, preconditioning with tunicamycin or thapsigargin enhances the UPR and ameliorates renal dysfunction and damage when full‐blown ER stress arises [Prachasilchai et al., ].…”

“…There is now clear evidence that ER stress targets renal cells and actively participate in the development of AKI and progression to CKD. Notably, transducers of the UPR, like the IRE1α‐sXBP1 axis, or the PERK‐CHOP pathways play a critical role in mediating the response to ER stress upon kidney injuries to cell death, inflammation and fibrogenesis [El Karoui et al., ; Fan et al., ; Inagi et al., ; Johnson et al., ; Mami et al., ; Mami et al., ]. A wide range of biological disturbances, virtually all of which are encountered upon AKI, induce ER stress, including increased levels of protein synthesis, deficient autophagy, energy deprivation, excess or limited nutrients, deregulated calcium levels, perturbations of redox homeostasis, inflammatory challenges and hypoxia [Wang and Kaufman, ].…”