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REDD1
Regulated in development and DNA damage-response 1 (REDD1 also known as Ddit4, Dig2, RTP801) is a stress-responsive protein that controls various cellular functions, including metabolism, oxidative stress, autophagy, and cell fate. Expression of REDD1 is upregulated in a multitude of pathologies and we now know that it contributes to the pathogenesis of metabolic and inflammatory disorders, neurodegeneration, and cancer.
Diabetic Retinopathy
Diabetic retinopathy (DR) is a significant ocular complication caused by diabetes that leads to blindness. Despite significant advances in therapeutic approaches to treat DR, it remains the most frequent cause of new cases of blindness in developed countries. A major limitation to current therapies are that they largely address the microvascular dysfunction and neovascularization that characterize later stages of DR progression. However, neuro-glial deficits can precede and often even predict the visible signs of microvascular disease in diabetic patients. There is thus a significant need for novel therapeutics that are preventative and/or provide interventions earlier in the preclinical and non-proliferative stages of DR by targeting the initiating events that cause retinal pathology.
Our laboratory has demonstrated that the stress response protein Regulated in Development and DNA Damage 1 (REDD1, also known as RTP801/DDIT4) is upregulated in Müller glia in multiple preclinical models of diabetes, and is necessary for diabetes-induced retinal pathology and functional vision defects. Our research has demonstrated that REDD1 expression in Müller glia is a key regulator for the development of oxidative stress and inflammation; well established mechanisms of retinal injury in the context of DR.
Click the below links to learn more about REDD1 in the context of Diabetic Retinopathy
Diabetic Nephropathy
Diabetic nephropathy (DN) is one of the most common and severe complications of diabetes and causes increased morbidity and mortality in diabetic patients. Approximately half of all patients with type 2 diabetes and one-third with patients with type 1 diabetes will develop chronic kidney disease, which is clinically defined by disruption of the glomerular filtration barrier (GFB) and albuminuria. Presently, there is an unmet clinical need for therapeutics that are preventative and/or provide interventions in the early stages of DN progression. The pathogenesis of DN is complex and multi-factorial; however, it is well accepted that podocyte defects and immune cell activation are crucial factors in the development and progression of renal complications.
Independent investigations by our laboratory and others have provided evidence that the stress response protein Regulated in Development and DNA Damage 1 (REDD1, also known as RTP801/DDIT4) may play a significant role in the development of renal function deficits in DN. Notably a strong correlation between REDD1 expression and renal injury has been observed in diabetic patients with chronic kidney disease (Mu et al. 2022). Our laboratory has demonstrated that hyperglycemia-induced REDD1 expression in the kidneys of diabetic mice contributes to the development of renal pathology and filtration function deficits. Importantly our research suggests a potential role for REDD1 in regulation of oxidative stress and inflammation mechanisms that result in increased renal injury and function defects.
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Hormone influence on mTORC1/2 mediated protein synthesis
Activation of the protein kinase mTOR (mechanistic target of rapamycin) in both complexes 1 and 2 (mTORC1/2) in the liver is repressed during fasting and rapidly stimulated in response to feeding. The effect of a meal on hepatic mTORC1/2 is attributed to an increase in plasma levels of nutrients, such as amino acids, and insulin. By contrast, fasting is associated with elevated plasma levels of glucagon, which is conventionally viewed as having a counter-regulatory role to insulin. I investigated the impact of insulin and glucagon on mTORC1/2 activation in rat H4IIE and human HepG2 cell cultures. As expected, insulin enhanced phosphorylation of the mTORC1 substrates S6K1 and 4E-BP1. Surprisingly, the effect of glucagon on mTORC1 signaling was biphasic, wherein there was an acute increase in phosphorylation of mTORC1 sensitive targets, S6K1 and 4E-BP1 over the first hour of exposure, followed by latent suppression. Notably, the stimulatory effect of glucagon on mTORC1 was not additive with insulin, suggesting a convergent signaling axis. I also discovered that glucagon elicits this acute activation of hepatic mTORC1/2 by an EPAC-dependent increase in Rap1-GTP.
Effects of the flavonoid Chrysin on Cyclosporine A-Nephropathy
Chrysin attenuates cyclosporine A-induced renal fibrosis.
Mason's Trichrome staining of kidneys (Image credit: Mumtaz Akhtar Ph.D.)
Cyclosporine (CsA) associated kidney toxicology has been well documented over the decades. CsA-induced epithelial mesenchymal transition is hypothesized to be a significant contributor towards the development of tubulointerstitial fibrosis. We discovered that the plant flavonoid chrysin processes anti-EMT properties that prevent the development of renal fibrosis in rodents treated with CsA. We further elucidated the molecular mechanism by which chrysin impedes development of fibrosis in proximal tubule cells showing that chrysin inhibits CsA-induced TGF-β mediated EMT by influencing both Smad and non-Smad dependent pathways. These studies contribute to our understanding of molecular events contributing to chronic renal fibrosis and advocate for the use and further development of flavonoids as a therapeutic intervention.
Characterizing media substrate influences on cell phenotype and energetics
With increasing use of in vitro techniques to address pharmacology and toxicology end points it becomes important to address cellular environments that influence cell phenotype. Most cell culture models utilize culture media containing high glucose concentrations. Studies using proximal tubule cells cultured in elevated glucose concentrations revealed a decreased trafficking of proteins to the plasma membrane resulting in reduced glucose uptake. We demonstrated that glucose in culture media influenced intracellular cAMP signaling and showed that the decreased trafficking of membrane proteins was regulated by a PKA/p38MAPK signaling axis.
Culture media supplemented with acetoacetate revealed an increase in mitochondrial oxidative activity with a concomitant increase in mitochondrial protein. Examination of the resulting phenotype change revealed an increased sensitivity towards mitochondrial toxicants, creating a better in vitro model to study the effects of renal toxicants.
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