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Genetic deficiency of adiponectin protects against acute kidney injury.

ABSTRACT: Adiponectin is a multifunctional cytokine that has a role in regulating inflammation. Here we determined whether adiponectin modulates ischemic acute kidney injury. Compared with wild-type mice, adiponectin-knockout mice were found to have lower serum creatinine and less tubular damage or apoptosis following ischemia/reperfusion injury. This latter process was associated with decreased Bax and reduced activation of p53 and caspase-3. Targeted disruption of adiponectin was also found to inhibit the infiltration of neutrophils, macrophages, and T cells into the injured kidneys. This was associated with inhibition of NF-?B activation and reduced expression of the proinflammatory molecules IL-6, TNF-?, MCP-1, and MIP-2 in the kidney after ischemia/reperfusion injury. Wild-type mice engrafted with adiponectin-null bone marrow had less kidney dysfunction and tubular damage than adiponectin-null mice engrafted with wild-type bone marrow. Conversely, adiponectin-null mice engrafted with wild-type bone marrow had similar renal dysfunction and tubular damage compared with wild-type mice engrafted with wild-type bone marrow. In cultured macrophages, adiponectin directly promoted macrophage migration: a process blocked by the PI3 kinase inhibitor, LY294002. Thus, our results show that adiponectin has a pivotal role in the pathogenesis of acute renal ischemia/reperfusion injury and may be a potential therapeutic target.

SUBMITTER: Jin X

PROVIDER: S-EPMC3612389 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Genetic deficiency of adiponectin protects against acute kidney injury.

Jin Xiaogao X Chen Jiyuan J Hu Zhaoyong Z Chan Lawrence L Wang Yanlin Y

Kidney international 20130109 4

Adiponectin is a multifunctional cytokine that has a role in regulating inflammation. Here we determined whether adiponectin modulates ischemic acute kidney injury. Compared with wild-type mice, adiponectin-knockout mice were found to have lower serum creatinine and less tubular damage or apoptosis following ischemia/reperfusion injury. This latter process was associated with decreased Bax and reduced activation of p53 and caspase-3. Targeted disruption of adiponectin was also found to inhibit t ...[more]

PMID: 23302722

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Project description:BackgroundInterleukin-17C (IL-17C), a member of the IL-17 cytokine family, plays a pathogenic role in kidney diseases. Our previous studies have shown that pre-administration of IL-17C neutralizing antibody attenuated acute kidney injury (AKI, a common acute inflammation associated renal disease). In this study, we explored whether post-ischemia reperfusion (IR) of IL-17C blockade has therapeutic effects on AKI and whether IL-17C is involved in the pathogenesis of diabetic nephropathy (DN), a major type of chronic inflammation-associated kidney disease.Methods12-week-old male C57BL/6JGpt mice were treated with IL-17C neutralizing antibody or normal IgG control antibody at 3 h after reperfusion. Renal injury, inflammation, and oxidative stress were assessed. Additionally, we examined renal IL-17C expression in patients with DN and db/db mice and evaluated albuminuria, mesangial matrix accumulation and podocyte loss in db/db mice with IL-17C neutralization. Knockdown of NF-κB p65 using siRNA, and blocking Hypoxia-inducible factor-1α (HIF-1α) using YC-1 in mice and HIF-1α Decoy in HK2 cells were investigated to explore the possible signaling pathway involved in IL-17C regulation.FindingsWe found that delayed IL-17C neutralization had similar reno-protective effects on renal ischemia-reperfusion injury (IRI). Additionally, renal IL-17C expression was increased in patients with DN and db/db mice, while IL-17C blockade significantly attenuated DN, accompanied with blunted albuminuria, mesangial matrix accumulation, and podocyte loss. Moreover, IL-17C neutralization significantly repressed the expression of downstream pro-inflammatory cytokines, inflammatory cell infiltration, and Th17/IL-17A activation both in mice with renal IRI and DN. Mechanistical studies demonstrated that hypoxia or high glucose-induced IL-17C up-regulation was predominantly mediated by NF-κB pathway.InterpretationIL-17C participates in the pathogenesis of AKI and DN and inhibition of IL-17C shows potential as a therapeutic strategy for AKI and DN.FundingThe National Natural Science Foundation of China (81770741, 81700601 and 81870504).

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Genetic deficiency of adiponectin protects against acute kidney injury.

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Genetic deficiency of adiponectin protects against acute kidney injury.

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