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In vivo AAV delivery of glutathione reductase gene attenuates anti-aging gene klotho deficiency-induced kidney damage.

ABSTRACT: OBJECTIVE:Klotho is an aging-suppressor gene which leads to accelerated aging when disrupted. This study was designed to investigate whether glutathione reductase (GR), a critical intracellular antioxidant enzyme, is involved in the pathogenesis of kidney damages associated with accelerated aging in Klotho-haplodeficient (KL+/-) mice. METHODS AND RESULTS:Klotho-haplodeficient (KL+/-) mice and WT mice were used. We found that Klotho haplodeficiency impaired kidney function as evidenced by significant increases in plasma urea and creatinine and a decrease in urinary creatinine in KL+/- mice. The expression and activity of GR was decreased significantly in renal tubular epithelial cells of KL+/- mice, suggesting that Klotho deficiency downregulated GR. We constructed adeno-associated virus 2 (AAV2) carrying GR full-length cDNA (AAV-GR). Interestingly, in vivo AAV-GR delivery significantly improved Klotho deficiency-induced renal functional impairment and structural remodeling. Furthermore, in vivo expression of GR rescued the downregulation of the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, which subsequently diminished oxidative damages in kidneys, as evidenced by significant decreases in renal 4-HNE expression and urinary 8-isoprostane levels in KL mice. CONCLUSION:This study provides the first evidence that Klotho deficiency-induced kidney damage may be partly attributed to downregulation of GR expression. In vivo delivery of AAV-GR may be a promising therapeutic approach for aging-related kidney damage.

SUBMITTER: Gao D

PROVIDER: S-EPMC7476318 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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In vivo AAV delivery of glutathione reductase gene attenuates anti-aging gene klotho deficiency-induced kidney damage.

Gao Diansa D Wang Shirley S Lin Yi Y Sun Zhongjie Z

Redox biology 20200820

<h4>Objective</h4>Klotho is an aging-suppressor gene which leads to accelerated aging when disrupted. This study was designed to investigate whether glutathione reductase (GR), a critical intracellular antioxidant enzyme, is involved in the pathogenesis of kidney damages associated with accelerated aging in Klotho-haplodeficient (KL<sup>+/-</sup>) mice.<h4>Methods and results</h4>Klotho-haplodeficient (KL<sup>+/-</sup>) mice and WT mice were used. We found that Klotho haplodeficiency impaired ki ...[more]

PMID: 32863229

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Project description:ObjectiveRheumatoid arthritis (RA) is the most common form of autoimmune inflammatory arthritis. Intra-articular gene delivery to block proinflammatory cytokines has been studied in pre-clinical models and human clinical trials. It has been demonstrated that the level of programmed death-ligand 1 (PD-L1) is associated with rheumatoid arthritis (RA). This study examined the therapeutic role of PD-L1 by intra-articular delivery via adeno-associated virus (AAV) vectors in the mouse collagen-induced arthritis (CIA) model.MethodsMice were intra-articularly injected with AAV5 vectors encoding human PD-L1 on day 0 and immunized with bovine type II collagen to induce CIA simultaneously. On day 49 post AAV administration, joints were collected for histo-pathological and cytokine analysis. Additionally, the systemic impacts of intra-articular injection of AAV5/PD-L1 vectors were also studied. To study the therapeutic effect of PD-L1, AAV5/PD-L1 vectors were administered into the joints of RA mice on day 21.ResultsAfter administration of AAV5/PD-L1 vectors, strong PD-L1 expression was detected in AAV transduced joints. Joints treated with PD-L1 at the time of arthritis induction exhibited significantly less swelling and improved histopathological scores when compared to untreated joints. Additionally, the infiltration of T cells and macrophages was decreased in joints of CIA mice that received AAV5/PD-L1 vectors (P<0.05). The levels of pro-inflammatory cytokines, including IL-1, IL-6, IL-17 and TNFα, were lower in AAV5/PD-L1 treated than untreated joints (P<0.05). Furthermore, the administration of AAV5/PD-L1 vectors into the joints of CIA mice did not impact serum cytokine levels and the antibody titers to type II collagen. Biodistribution of AAV vectors after intra-articular injection showed undetectable AAV genomes in other tissues except for a low level in the liver. Similar to the results of AAV5/PD-L1 vector administration on day 0, decreased joint swelling and lower histopathological damage were observed in joints treated with AAV5/PD-L1 vectors on day 21.ConclusionThe results from this study demonstrate that local AAV mediated PD-L1 gene delivery into the joints is able to prevent the development and block the progression of arthritis in CIA mice without impacting systemic immune responses. This study provides a novel strategy to effectively treat inflammatory joint diseases using local AAV gene therapy by interference with immune checkpoint pathways.

Dataset Information

In vivo AAV delivery of glutathione reductase gene attenuates anti-aging gene klotho deficiency-induced kidney damage.

Publications

In vivo AAV delivery of glutathione reductase gene attenuates anti-aging gene klotho deficiency-induced kidney damage.

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