Publications by authors named "Siddharth Sunilkumar"
Rapid proteasomal degradation of the stress response protein REDD2 is mediated by the E3 ligase HUWE1.
Biochem Biophys Res Commun
September 2025
The stress response proteins regulated in development and DNA damage (REDD)1 and REDD2 act as negative regulators of mechanistic target of rapamycin complex 1 (mTORC1). Prior studies support that REDD1 is rapidly degraded via both chaperone-mediated autophagy (CMA) and the ubiquitin proteasome system (UPS). Compared to REDD1, relatively little is known regarding the regulation of REDD2.
View Article and Find Full Text PDFSterile inflammation resulting in an altered immune response is a key determinant of renal injury in diabetic nephropathy (DN). In this investigation, we evaluated the hypothesis that hyperglycemic conditions augment the pro-inflammatory immune response in the kidney by promoting podocyte-specific expression of the stress response protein regulated in development and DNA damage response 1 (REDD1). In support of the hypothesis, streptozotocin (STZ)-induced diabetes increased REDD1 protein abundance in the kidney concomitant with renal immune cell infiltration.
View Article and Find Full Text PDFIncreasing evidence supports the role of an augmented immune response in the early development and progression of renal complications caused by diabetes. We recently demonstrated that podocyte-specific expression of stress response protein regulated in development and DNA damage response 1 (REDD1) contributes to activation of the pro-inflammatory transcription factor NF-κB in the kidney of diabetic mice. The studies here were designed to define the specific signaling events whereby REDD1 promotes NF-κB activation in the context of diabetic nephropathy.
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- Age-related macular degeneration (AMD) is a significant cause of blindness in older adults, but the initial molecular changes that lead to vision loss are not well understood.
- Research using sodium iodate (NaIO) on mice showed increased levels of the stress response protein REDD1 in the retina, which correlates with heightened oxidative stress and inflammation when NaIO is administered.
- Mice without REDD1 experienced less damage, including reduced oxidative stress and preserved retinal structure, suggesting that REDD1 plays a crucial role in developing retinal issues associated with dry AMD.
Article Synopsis
- Diabetic nephropathy (DN) is a major cause of kidney failure, and this study focuses on the stress response protein REDD1's role in podocytes during diabetes.
- Researchers found that deleting REDD1 specifically in podocytes reduced kidney damage in diabetic mice, shown by lower levels of albuminuria and preserved kidney structure.
- The study highlights that REDD1 is crucial for the effects of diabetes on certain kidney proteins and suggests that targeting REDD1 could lead to new treatments for DN.
The stress response protein regulated in development and DNA damage response 1 (REDD1) has emerged as a key player in the pathogenesis of diabetes. Diabetes upregulates REDD1 in a variety of insulin-sensitive tissues, where the protein acts to inhibit signal transduction downstream of the insulin receptor. REDD1 functions as a cytosolic redox sensor that suppresses Akt/mTORC1 signaling to reduce energy expenditure in response to cellular stress.
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- Activation of NF-κB in heart cells (cardiomyocytes) is linked to heart function issues in diabetes, primarily through the production of inflammatory proteins.
- The protein REDD1 is crucial for increasing these inflammatory proteins in diabetic hearts, as its absence leads to decreased NF-κB signaling and reduced expression of pro-inflammatory cytokines.
- In diabetic mice, REDD1 influences heart function by affecting GSK3β activity, with its presence linked to serious cardiac dysfunction, whereas REDD1 deficiency appears to protect against diabetes-related heart problems.
NLRP3 Inflammasome Priming in the Retina of Diabetic Mice Requires REDD1-Dependent Activation of GSK3β.
Invest Ophthalmol Vis Sci
March 2024
Article Synopsis
- This study investigates how diabetes triggers the activation of the NLRP3 inflammasome, a key player in retinal complications associated with diabetes.
- Researchers found that both NLRP3 and interleukin-1β (IL-1β) levels increased in diabetic mice and cultured Müller cells under hyperglycemic conditions, with the stress response protein REDD1 being essential for this increase.
- The findings suggest that REDD1 influences GSK3β activity, which is crucial for NLRP3 inflammasome activation and IL-1β production in Müller glial cells during diabetes, potentially affecting visual function in diabetic mice.
Article Synopsis
- Inflammation plays a significant role in the development and progression of diabetic retinal complications, with REDD1 being a key protein involved in this process.
- REDD1 promotes the activation of NF-κB, a transcription factor linked to inflammation, by affecting the phosphorylation of GSK3β, particularly under hyperglycemic conditions.
- Inhibiting GSK3β in diabetic models can reduce NF-κB activity and pro-inflammatory cytokine expression, suggesting potential therapeutic avenues for managing diabetic retinal inflammation.
Endoplasmic reticulum (ER) stress and inflammation are hallmarks of myocardial impairment. Here, we investigated the role of the stress response protein regulated in development and DNA damage 1 (REDD1) as a molecular link between ER stress and inflammation in cardiomyocytes. In mice fed a high-fat high-sucrose (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 wk, REDD1 expression in the heart was increased in coordination with markers of ER stress and inflammation.
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- Inflammation in the retina is worsened by diabetes, and the study investigates the role of a stress response protein called REDD1 in this process.
- Increased levels of REDD1 were found in the retinas of diabetic mice, and it was essential for the expression of inflammatory cytokines.
- Deleting REDD1 in human retinal cells inhibited these cytokines by affecting the NF-κB signaling pathway, demonstrating that REDD1 is a key player in diabetic retinal inflammation.
Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes.
Invest Ophthalmol Vis Sci
October 2022
Purpose: Neuroglial dysfunction occurs early in the progression of diabetic retinopathy. In response to diabetes or hypoxia, Müller glia secrete cytokines and growth factors that contribute to disease progression. This study was designed to examine common signaling pathways activated in Müller glia by both type 1 and pre-/type 2 diabetes.
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- REDD1, a stress response protein, is linked to visual deficits in diabetes, with increased levels observed in the retinas of diabetic mice, despite no changes in its mRNA or ribosome association.
- Oral antioxidants were found to lower oxidative stress and REDD1 protein levels, indicating a potential therapeutic pathway for managing retinal issues in diabetes.
- The study uncovered that high glucose conditions led to oxidative stress, enhancing REDD1 expression and stability through disulfide bond formation, impacting its degradation and highlighting a complex regulatory mechanism involving redox status.
Article Synopsis
- Chronic hyperglycemia leads to diabetic kidney disease by causing glomerular injury, with the protein REDD1 playing a key role in this process.
- A study showed that wild-type mice with diabetes displayed increased REDD1 expression and renal damage, while diabetic mice lacking REDD1 had better kidney health and less injury.
- In human kidney cells, hyperglycemia raised REDD1 levels, leading to oxidative stress and cell death, but deleting REDD1 or inhibiting GSK3β improved cell survival and reduced damage.
Article Synopsis
- Clinical studies suggest that the protein REDD1 is involved in retinal issues caused by ischemia and diabetes, particularly in Müller glia cells.
- Researchers used REDD1-specific knockout mice to show that without REDD1, oxidative stress and gliosis (a type of cell reaction in the retina) are reduced in diabetic conditions, which helps preserve retinal health.
- Findings indicate that REDD1 in Müller glia is crucial for the retina's detrimental responses to diabetes, leading to complications like neurodegeneration and vision problems that are not observed in REDD1-deficient mice.
Cyclosporine A (CsA) is a nephrotoxicant that causes fibrosis via induction of epithelial-mesenchymal transition (EMT). The flavonoid chrysin has been reported to have anti-fibrotic activity and inhibit signaling pathways that are activated during EMT. This study investigated the nephroprotective role of chrysin in the prevention of CsA-induced renal fibrosis and elucidated a mechanism of inhibition against CsA-induced EMT in proximal tubule cells.
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- Activation of mTORC1/2 in the liver is inhibited during fasting but stimulated after eating, primarily due to increased nutrients and insulin levels.
- Fasting raises glucagon levels, which traditionally oppose insulin, yet recent findings reveal glucagon positively influences post-meal metabolism and mTORC1 activation.
- Experiments show that insulin promotes mTORC1 activation while glucagon has a mixed effect, initially stimulating and later inhibiting mTORC1, likely through an EPAC-dependent mechanism involving the small GTPase Rap1.
The stress response protein REDD1 as a causal factor for oxidative stress in diabetic retinopathy.
Free Radic Biol Med
March 2021
Article Synopsis
- * The stress response protein REDD1 plays a crucial role in the development of DR by both increasing oxidative stress and impacting vision, primarily through its interaction with the mTORC1 metabolic regulator.
- * Emerging clinical trials suggest that targeting REDD1 with siRNA could help treat diabetic eye diseases, indicating its potential as a novel therapeutic approach beyond just symptom management of diabetes.
Retinol-binding protein 4 mRNA translation in hepatocytes is enhanced by activation of mTORC1.
Am J Physiol Endocrinol Metab
February 2021
Increased expression of the peptide hormone retinol-binding protein 4 (RBP4) has been implicated in the development of insulin resistance, type 2 diabetes, and visual dysfunction. Prior investigations of the mechanisms that influence RBP4 synthesis have focused solely on changes in mRNA abundance. Yet, the production of many secreted proteins is controlled at the level of mRNA translation, as it allows for a rapid and reversible change in expression.
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- Activation of CD40 in Müller glia is linked to diabetes-induced retinal inflammation, with elevated CD40 protein in diabetic mice showing a need for further investigation into the underlying mechanisms.
- Treatment with thiamet G (TMG) enhances retinal protein -GlcNAcylation and boosts mRNA translation by affecting ribosomal interactions specific to Müller cells, observed in both normal and diabetic mouse retinas.
- The study suggests that diabetes increases -GlcNAcylation of 4E-BP1, which further enhances mRNA translation in Müller glia, potentially linking this process to the inflammatory response in diabetic retinopathy.
Article Synopsis
- Nrf2 is a key transcription factor that helps protect against oxidative stress by promoting antioxidant gene expression, but its activation is defective in people with diabetes and in diabetic mice models.
- The study found that the protein REDD1 is crucial for the oxidative stress development in diabetic retinas, as it suppresses Nrf2 function, leading to reduced antioxidant response.
- By removing REDD1, researchers observed increased Nrf2 activity and stability, and inhibiting GSK3 also boosted Nrf2 and lessened oxidative stress in diabetic conditions, indicating that REDD1 exacerbates oxidative damage by degrading Nrf2 through GSK3 activation.
Article Synopsis
- Cultured kidney cells in high glucose media show increased glycolytic activity, while normal renal proximal tubules use ketone bodies and focus on mitochondrial energy production.
- This study examines how adding the ketone body acetoacetate affects the metabolism of LLC-PK cells, revealing significant increases in various types of respiration and mitochondrial biomarkers.
- Results show that acetoacetate supplementation alters cell metabolism, leading to heightened sensitivity to certain drugs and toxins.
Article Synopsis
- * It was found that LLC-PK cells grown in high glucose (17.5 mM) had significantly lower SGLT activity compared to those in lower glucose concentrations, with SGLT2 identified as the main transporter involved.
- * The decrease in SGLT2 activity was linked to reduced trafficking of the transporter to the cell membrane, influenced by changes in intracellular cAMP and p38 MAPK signaling, which can be reversed with specific treatments.