Abstract
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.
Highlights
Diabetic nephropathy is the leading cause of end-stage renal disease and the strongest predictor of mortality in diabetic patients worldwide[1]
We previously demonstrated that increased reactive oxygen species (ROS) generation causes renal inflammasome activation and dNP22
To gain insight into the mechanism underlying the nephroprotective effect of minocycline in diabetic nephropathy (dNP) we compared the efficacy of minocycline (5 mg/kg, intraperitoneal, i.p.) with that of the caspase-inhibitor CIX
Summary
Diabetic nephropathy (dNP) is the leading cause of end-stage renal disease and the strongest predictor of mortality in diabetic patients worldwide[1]. To stimulate an antioxidant response Nrf[2] dimerizes with members of the small Maf family or c-Jun and binds to antioxidant response elements (AREs) in the regulatory regions of cellular cytoprotective proteins, such as glutathione enzymes (glutathione reductase, microsomal glutathione S-transferase 2), heme metabolism enzymes (heme oxygenase 1, ferrochelatase) or antioxidant enzymes (manganese superoxide dismutase (MnSOD), peroxiredoxin 1, thioredoxin reductase 1)[8,9] This allows Nrf[2] to efficiently initiate a cytoprotective response and prevent increased oxidative stress and further cellular damage. We hypothesized that minocycline protects from dNP independent of apoptosis-inhibition by restricting excess ROS-generation potentially via a Nrf2-dependent mechanism, preventing inflammasome activation in dNP
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