ApoL1 induces kidney inflammation through RIG-I/NF-κB activation

Yao, Xingmei; Hou, Meiying; Duan, Miao; Xing, Lina; Huang, Jiebo; Wang, Yunman; Zhu, Bin; Chen, Qiujing; Wang, Hao

doi:10.1016/j.bbrc.2020.04.054

Cited by 16 publications

(11 citation statements)

References 31 publications

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“…In line with these results, it was demonstrated that retinoic acid-inducible gene I (RIG-I) also recognizes HIV and enhances APOL1 expression and also activation of nuclear factor kappa B (NFкB). The knockdown of RIG-I in human podocytes resulted in attenuated inflammatory and apoptotic effects of APOL1 ( 44 ). Additionally, TLR 3 signaling, that can be activated by double stranded RNAs, can be found in replication cycles of nearly all viruses and was shown to enhance APOL1 expression INF-independent via NFкB-signaling ( 34 ).…”

Section: Hiv-associated Cfsgsmentioning

confidence: 99%

Collapsing Focal Segmental Glomerulosclerosis in Viral Infections

et al. 2022

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Collapsing glomerulopathy represents a special variant of the proteinuric kidney disease focal segmental glomerulosclerosis (FSGS). Histologically, the collapsing form of FSGS (cFSGS) is characterized by segmental or global condensation and obliteration of glomerular capillaries, the appearance of hyperplastic and hypertrophic podocytes and severe tubulointerstitial damage. Clinically, cFSGS patients present with acute kidney injury, nephrotic-range proteinuria and are at a high risk of rapid progression to irreversible kidney failure. cFSGS can be attributed to numerous etiologies, namely, viral infections like HIV, cytomegalovirus, Epstein–Barr-Virus, and parvovirus B19 and also drugs and severe ischemia. Risk variants of the APOL1 gene, predominantly found in people of African descent, increase the risk of developing cFSGS. Patients infected with the new Corona-Virus SARS-CoV-2 display an increased rate of acute kidney injury (AKI) in severe cases of COVID-19. Besides hemodynamic instability, cytokine mediated injury and direct viral entry and infection of renal epithelial cells contributing to AKI, there are emerging reports of cFSGS associated with SARS-CoV-2 infection in patients of mainly African ethnicity. The pathogenesis of cFSGS is proposed to be linked with direct viral infection of podocytes, as described for HIV-associated glomerulopathy. Nevertheless, there is growing evidence that the systemic inflammatory cascade, activated in acute viral infections like COVID-19, is a major contributor to the impairment of basic cellular functions in podocytes. This mini review will summarize the current knowledge on cFSGS associated with viral infections with a special focus on the influence of systemic immune responses and potential mechanisms propagating the development of cFSGS.

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Section: Hiv-associated Cfsgsmentioning

confidence: 99%

Collapsing Focal Segmental Glomerulosclerosis in Viral Infections

et al. 2022

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“…Recent research indicated that in the absence of viral infection, RIG-I could also be activated by a pattern recognition receptor in kidney-related inflammatory diseases [ 14 , 39 , 40 ]. Simultaneously, the relationship between RIG-I and traumatic diseases has been reported.…”

Section: Discussionmentioning

confidence: 99%

RIG-I, a novel DAMPs sensor for myoglobin, activates NF-κB/caspase-3 signaling in CS-AKI model

Wang

et al. 2021

Military Med Res

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Background Acute kidney injury (AKI) is the main life-threatening complication of crush syndrome (CS), and myoglobin is accepted as the main pathogenic factor. The pattern recognition receptor retinoicacid-inducible gene I (RIG-I) has been reported to exert anti-viral effects function in the innate immune response. However, it is not clear whether RIG-I plays a role in CS-AKI. The present research was carried out to explore the role of RIG-I in CS-AKI. Methods Sprague-Dawley rats were randomly divided into two groups: the sham and CS groups (n = 12). After administration of anesthesia, the double hind limbs of rats in the CS group were put under a pressure of 3 kg for 16 h to mimic crush conditions. The rats in both groups were denied access to food and water. Rats were sacrificed at 12 h or 36 h after pressure was relieved. The successful establishment of the CS-AKI model was confirmed by serum biochemical analysis and renal histological examination. In addition, RNA sequencing was performed on rat kidney tissue to identify molecular pathways involved in CS-AKI. Furthermore, NRK-52E cells were treated with 200 μmol/L ferrous myoglobin to mimic CS-AKI at the cellular level. The cells and cell supernatant samples were collected at 6 h or 24 h. Small interfering RNAs (siRNA) was used to knock down RIG-I expression. The relative expression levels of molecules involved in the RIG-I pathway in rat kidney or cells samples were measured by quantitative Real-time PCR (qPCR), Western blotting analysis, and immunohistochemistry (IHC) staining. Tumor necrosis factor-α (TNF-α) was detected by ELISA. Co-Immunoprecipitation (Co-IP) assays were used to detect the interaction between RIG-I and myoglobin. Results RNA sequencing of CS-AKI rat kidney tissue revealed that the different expression of RIG-I signaling pathway. qPCR, Western blotting, and IHC assays showed that RIG-I, nuclear factor kappa-B (NF-κB) P65, p-P65, and the apoptotic marker caspase-3 and cleaved caspase-3 were up-regulated in the CS group (P < 0.05). However, the levels of interferon regulatory factor 3 (IRF3), p-IRF3 and the antiviral factor interferon-beta (IFN-β) showed no significant changes between the sham and CS groups. Co-IP assays showed the interaction between RIG-I and myoglobin in the kidneys of the CS group. Depletion of RIG-I could alleviate the myoglobin induced expression of apoptosis-associated molecules via the NF-κB/caspase-3 axis. Conclusion RIG-I is a novel damage-associated molecular patterns (DAMPs) sensor for myoglobin and participates in the NF-κB/caspase-3 signaling pathway in CS-AKI. In the development of CS-AKI, specific intervention in the RIG-I pathway might be a potential therapeutic strategy for CS-AKI.

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“…Further evidence for this mechanism includes another study that showed that the upregulation of retinoic acid-inducible gene I (RIG-I) and nuclear factor kappa B (NF-jΒ) was also associated with increased intracellular ApoL1 production [41]. RIG-I has been shown to 'sense' HIV infection and mediates transcriptional activation of type 1 IFN, and IFN has been described as an activator of NF-jΒ [42].…”

Section: Hiv Upregulates Apol1 In Podocytesmentioning

confidence: 99%

APOL1 risk variants and the development of HIV‐associated nephropathy

Goyal

Singhal

2020

The FEBS Journal

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HIV-associated nephropathy (HIVAN) remains a concern among untreated HIV patients, notably of African descent, as patients can reach end-stage renal disease within 3 years. Two variants (G1 and G2) of the APOL1 gene, common in African populations to protect against African sleeping sickness, have been associated with an increased risk of several glomerular disorders including HIVAN, hypertension-attributed chronic kidney disease, and idiopathic focal segmental glomerulosclerosis and are accordingly named renal risk variants (RRVs). This review examines the mechanisms by which APOL1 RRVs drive glomerular injury in the setting of HIV infection and their potential application to patient management. Innate antiviral mechanisms activated by chronic HIV infection, especially those involving type 1 interferons, are of particular interest as they have been shown to upregulate APOL1 expression. Additionally, the downregulation of miRNA 193a (a repressor of APOL1) is also associated with the upregulation of APOL1. Interestingly, glomerular damage affected by APOL1 RRVs is caused by both loss-and gain-of-function changes in the protein, explicitly characterizing these effects. Their intracellular localization offers a further understanding of the nuances of APOL1 variant effects in promoting renal disease. Finally, although APOL1 variants have been recognized as a critical genetic player in mediating kidney disease, there are significant gaps in their application to patient management for screening, diagnosis, and treatment.

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ApoL1 induces kidney inflammation through RIG-I/NF-κB activation

Cited by 16 publications

References 31 publications

Collapsing Focal Segmental Glomerulosclerosis in Viral Infections

Collapsing Focal Segmental Glomerulosclerosis in Viral Infections

RIG-I, a novel DAMPs sensor for myoglobin, activates NF-κB/caspase-3 signaling in CS-AKI model

APOL1 risk variants and the development of HIV‐associated nephropathy

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