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Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy.

ABSTRACT: Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow-derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.

SUBMITTER: Shahzad K

PROVIDER: S-EPMC4284813 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy.

Shahzad Khurrum K Bock Fabian F Dong Wei W Wang Hongjie H Kopf Stefan S Kohli Shrey S Al-Dabet Moh'd Mohanad MM Ranjan Satish S Wolter Juliane J Wacker Christian C Biemann Ronald R Stoyanov Stoyan S Reymann Klaus K Söderkvist Peter P Groß Olaf O Schwenger Vedat V Pahernik Sascha S Nawroth Peter P PP Gröne Herman-Josef HJ Madhusudhan Thati T Isermann Berend B

Kidney international 20140730 1

Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial ce ...[more]

PMID: 25075770

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Project description:Diabetic nephropathy (DN) is one of the most lethal complications of diabetes mellitus with metabolic disorders and chronic inflammation. Although the cytokine IL-22 was initially implicated in the pathogenesis of chronic inflammatory diseases, recent studies suggested that IL-22 could suppress inflammatory responses and alleviate tissue injury. Herein, we examined the role of IL-22 in DN. We found that serum levels of IL-22 were significantly downregulated in both patients and mice with DN. The expression of IL-22 was further decreased with the progression of DN, whereas IL-22 gene therapy significantly ameliorated renal injury and mesangial matrix expansion in mice with established nephropathy. IL-22 could also markedly reduce high glucose-induced and TGF-β1-induced overexpression of fibronectin and collagen IV in mouse renal glomerular mesangial cells in a dose-dependent manner, suggesting the potential role of IL-22 to inhibit the overproduction of ECM in vitro. Simultaneously, IL-22 gene therapy drastically alleviated renal fibrosis and proteinuria excretion in DN. In addition, IL-22 gene therapy markedly attenuated hyperglycemia and metabolic disorders in streptozotocin-induced experimental diabetic mice. Notably, IL-22 drastically reversed renal activation of NLRP3, cleavage of caspase-1, and the maturation of IL-1β in DN, suggesting unexpected anti-inflammatory function of IL-22 via suppressing the activation of NLRP3 inflammasome in vivo. Moreover, IL-22 markedly downregulated high glucose-induced activation of NLRP3 inflammasome in renal mesangial cells in a dose-dependent manner, indicating that the effects of IL-22 on NLRP3 inflammasome activation was independent of improved glycemic control. These results suggested that nephroprotection by IL-22 in DN was most likely associated with reduced activation of NLRP3 inflammasome. In conclusion, our finding demonstrated that IL-22 could exert favorable effects on DN via simultaneously alleviating systemic metabolic syndrome and downregulating renal NLRP3/caspase-1/IL-1β pathway, suggesting that IL-22 might have therapeutic potential for the treatment of DN.

Project description:Background and aimsDonors with fatty livers are considered to address the shortage of livers for transplantation, but those livers are particularly sensitive to ischemia-reperfusion injury (IRI), and an increased incidence of graft failure is observed. Kupffer cells account for 20-35% of liver nonparenchymal cells, and have been shown to participate in the process of IRI and inflammatory reactions of hepatic steatosis. NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) is an intracellular sensor activated by Kupffer cells to promote generation and participates in IRI. Dynamics-associated protein 1 (Drp1) is one of the main proteins regulating mitochondrial division and exacerbates IRI by affecting mitochondrial dynamics. The mechanism of interaction of Kupffer cells with Drp1 and NLRP3 to aggravate IRI has not been clarified.MethodsA mouse model of hepatic steatosis was established by feeding the mice with a high-fat diet. In vitro experiments were performed using AML12 normal mouse liver cells and RAW264.7 mononuclear macrophage cells cultured in medium with palmitate and oleic acid. Western blotting and immunohistochemical (IHC) staining were used to detect the expression of NLRPP3 and Drp1 in IRI in the control and high-fat diet groups. The expression of F4/80+ cells during IRI in hepatic steatosis was verified by IHC staining, and the role of NLRPP3 and Drp1 in Kupffer-cell mediated IRI was investigated by targeting Drp-1 inhibition.ResultsDrp1 and NLRP3 expression was increased during IRI in hepatic steatosis, and the expression of Drp1 and NLRP3 were decreased after the elimination of Kupffer cells. That indicated Kupffer cells were involved in the process of IRI in hepatic steatosis through the action of Drp1 and NLRP3. After Drp1 inhibition, liver function was restored and NLRP3 expression level was reduced.ConclusionsKupffer cells aggravated IRI in hepatic steatosis via NLRP3 and Drp1. Drp1 inhibitors might be useful as specific therapeutics to alleviate IRI in hepatic steatosis and may have promise in case of liver donor shortage.

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Dataset Information

Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy.

Publications

Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy.

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