Scientific reports, 2016-10, Vol.6 (1), p.34228-34228, Article 34228
2016
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- Autor(en) / Beteiligte
- Titel
- Stabilization of endogenous Nrf2 by minocycline protects against Nlrp3-inflammasome induced diabetic nephropathy
- Ist Teil von
- Scientific reports, 2016-10, Vol.6 (1), p.34228-34228, Article 34228
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2016
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- While a plethora of studies support a therapeutic benefit of Nrf2 activation and ROS inhibition in diabetic nephropathy (dNP), the Nrf2 activator bardoxolone failed in clinical studies in type 2 diabetic patients due to cardiovascular side effects. Hence, alternative approaches to target Nrf2 are required. Intriguingly, the tetracycline antibiotic minocycline, which has been in clinical use for decades, has been shown to convey anti-inflammatory effects in diabetic patients and nephroprotection in rodent models of dNP. However, the mechanism underlying the nephroprotection remains unknown. Here we show that minocycline protects against dNP in mouse models of type 1 and type 2 diabetes, while caspase -3,-6,-7,-8 and -10 inhibition is insufficient, indicating a function of minocycline independent of apoptosis inhibition. Minocycline stabilizes endogenous Nrf2 in kidneys of db/db mice, thus dampening ROS-induced inflammasome activation in the kidney. Indeed, minocycline exerts antioxidant effects in vitro and in vivo , reducing glomerular markers of oxidative stress. Minocycline reduces ubiquitination of the redox-sensitive transcription factor Nrf2 and increases its protein levels. Accordingly, minocycline mediated Nlrp3 inflammasome inhibition and amelioration of dNP are abolished in diabetic Nrf2 −/− mice. Taken together, we uncover a new function of minocycline, which stabilizes the redox-sensitive transcription factor Nrf2, thus protecting from dNP.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2045-2322eISSN: 2045-2322DOI: 10.1038/srep34228Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5056367
- Format
- –
- Schlagworte
- 13, 13/109, 13/95, 14, 14/34, 14/5, 14/63, 38/1, 38/22, 38/77, 38/90, 631/154/555, 631/443/272, 82/29, 82/51, 82/83, Animal models, Animals, Antibiotics, Apoptosis, Caspase, Diabetes, Diabetes mellitus, Diabetes Mellitus, Experimental - genetics, Diabetes Mellitus, Experimental - metabolism, Diabetes Mellitus, Experimental - prevention & control, Diabetic Nephropathies - genetics, Diabetic Nephropathies - metabolism, Diabetic Nephropathies - pathology, Diabetic Nephropathies - prevention & control, Diabetic nephropathy, Humanities and Social Sciences, Inflammasomes, Inflammasomes - metabolism, Inflammation, Kidneys, Mice, Mice, Knockout, Minocycline, Minocycline - pharmacology, multidisciplinary, Nephropathy, NF-E2-Related Factor 2 - genetics, NF-E2-Related Factor 2 - metabolism, NLR Family, Pyrin Domain-Containing 3 Protein - metabolism, Oxidative stress, Protein Stability - drug effects, Reactive oxygen species, Rodents, Science, Side effects, Transcription factors, Ubiquitination