Mechanisms and implications of podocyte autophagy in chronic kidney disease.

Autophagy is a protective mechanism through which cells degrade and recycle proteins and organelles to maintain cellular homeostasis and integrity. An accumulating body of evidence underscores the significant impact of dysregulated autophagy on podocyte injury in chronic kidney disease (CKD). In this review, we provide a comprehensive overview of the diverse types of autophagy and their regulation in cellular homeostasis, with a specific emphasis on podocytes. Furthermore, we discuss recent findings that focus on the functional role of different types of autophagy during podocyte injury in chronic kidney disease. The intricate interplay between different types of autophagy and podocyte health requires further research, which is critical for understanding the pathogenesis of CKD and developing targeted therapeutic interventions.

Oxysterol-binding protein-like 7 deficiency leads to ER stress-mediated apoptosis in podocytes and proteinuria.

Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein-like 7 (OSBPL7) modulates the expression and function of ATP-binding cassette subfamily A member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Using mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. Although as expected, the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7 deficiency-related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7 deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study sheds new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthens the role of OSBPL7 as a novel therapeutic target.NEW & NOTEWORTHY OSBPL7 and ER stress comprise a central mechanism in glomerular injury. This study highlights a crucial link between OSBPL7 deficiency and ER stress in CKD. OSBPL7 deficiency causes ER stress, leading to podocyte apoptosis. There is a selective effect on lipid homeostasis in that OSBPL7 deficiency affects lipid homeostasis, altering cellular triglyceride but not cholesterol content. The interaction of ER stress and apoptosis supports that ER stress, not reduced autophagy, is the main driver of apoptosis in OSBPL7-deficient podocytes.

COVID-19 and diabetes mellitus: how one pandemic worsens the other.

In light of the most challenging public health crisis of modern history, COVID-19 mortality continues to rise at an alarming rate. Patients with co-morbidities such as hypertension, cardiovascular disease, and diabetes mellitus (DM) seem to be more prone to severe symptoms and appear to have a higher mortality rate. In this review, we elucidate suggested mechanisms underlying the increased susceptibility of patients with diabetes to infection with SARS-CoV-2 with a more severe COVID-19 disease. The worsened prognosis of COVID-19 patients with DM can be attributed to a facilitated viral uptake assisted by the host's receptor angiotensin-converting enzyme 2 (ACE2). It can also be associated with a higher basal level of pro-inflammatory cytokines present in patients with diabetes, which enables a hyperinflammatory "cytokine storm" in response to the virus. This review also suggests a link between elevated levels of IL-6 and AMPK/mTOR signaling pathway and their role in exacerbating diabetes-induced complications and insulin resistance. If further studied, these findings could help identify novel therapeutic intervention strategies for patients with diabetes comorbid with COVID-19.

Role of the Nox4/AMPK/mTOR signaling axe in adipose inflammation-induced kidney injury.

Diabetic kidney disease is one of the most serious complications of diabetes worldwide and is the leading cause of end-stage renal disease. While research has primarily focused on hyperglycemia as a key player in the pathophysiology of diabetic complications, recently, increasing evidence have underlined the role of adipose inflammation in modulating the development and/or progression of diabetic kidney disease. This review focuses on how adipose inflammation contribute to diabetic kidney disease. Furthermore, it discusses in detail the underlying mechanisms of adipose inflammation, including pro-inflammatory cytokines, oxidative stress, and AMPK/mTOR signaling pathway and critically describes their role in diabetic kidney disease. This in-depth understanding of adipose inflammation and its impact on diabetic kidney disease highlights the need for novel interventions in the treatment of diabetic complications.

Novel triazine-based pyrimidines suppress glomerular mesangial cells proliferation and matrix protein accumulation through a ROS-dependent mechanism in the diabetic milieu.

Diabetic nephropathy (DN) is one of the most serious complications of diabetes worldwide. It is depicted as the leading cause of end-stage renal disease. Oxidative stress plays a key role in hyperglycemia-induced DN. The preparation and characterization of novel mono-, di-, and trisubstituted-s-triazines endowed with uracil and/or thymine are described in this paper. The synthesis of the title compounds was realized through selective nucleophilic substitution reactions of cyanuric chloride with the corresponding hydrazide nucleobases. In this study, we assessed the effects of these derivatives on the progression of diabetic nephropathy. Our results show that trisubstituted-s-triazines endowed with acylhydrazides attenuate high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. Notably, these derivatives also display anti-oxidative properties. This suggests that the novel trisubstituted-s-triazine derivatives provide renal protection through a reactive oxygen species (ROS)-dependent mechanism. Our data provide evidence that these derivatives may serve as potential therapeutic candidates in the treatment of DN.

Role of the Innate Immune Response in Glomerular Disease Pathogenesis: Focus on Podocytes.

Accumulating evidence indicates that inflammatory and immunologic processes play a significant role in the development and progression of glomerular diseases. Podocytes, the terminally differentiated epithelial cells, are crucial for maintaining the integrity of the glomerular filtration barrier. Once injured, podocytes cannot regenerate, leading to progressive proteinuric glomerular diseases. However, emerging evidence suggests that podocytes not only maintain the glomerular filtration barrier and are important targets of immune responses but also exhibit many features of immune-like cells, where they are involved in the modulation of the activity of innate and adaptive immunity. This dual role of podocytes may lead to the discovery and development of new therapeutic targets for treating glomerular diseases. This review aims to provide an overview of the innate immunity mechanisms involved in podocyte injury and the progression of proteinuric glomerular diseases.

Uncovering the Therapeutic Potential of Lithium Chloride in Type 2 Diabetic Cardiomyopathy: Targeting Tau Hyperphosphorylation and TGF-ß Signaling via GSK-3ß Inhibition.

Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus (T2DM) that leads to significant morbidity and mortality. The alteration in the signaling mechanism in diabetes leading to cardiomyopathy remains unclear. The purpose of this study is to investigate the role of tauopathy in myocardial dysfunction observed in T2DM. In that regard, diabetic Sprague Dawley rats were treated with intraperitoneal injections of lithium chloride (LiCl), inhibiting tau phosphorylation. Cardiac function was evaluated, and molecular markers of myocardial fibrosis and the TGF-ß signaling were analyzed. T2DM rats exhibited a decline in ejection fraction and fractional shortening that revealed cardiac function abnormalities and increased myocardial fibrosis. These changes were associated with tau hyperphosphorylation. Treating diabetic rats with LiCl attenuated cardiac fibrosis and improved myocardial function. Inhibition of GSK-3ß leads to the suppression of tau phosphorylation, which is associated with a decrease in TGF-ß expression and regulation of the pro-inflammatory markers, suggesting that tau hyperphosphorylation is parallelly associated with fibrosis and inflammation in the diabetic heart. Our findings provide evidence of a possible role of tau hyperphosphorylation in the pathogenesis of DCM through the activation of TGF-ß and by inducing inflammation. Targeting the inhibition of tau phosphorylation may offer novel therapeutic approaches to reduce DCM burden in T2DM patients.

Unraveling the Crosstalk between Lipids and NADPH Oxidases in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of end-stage renal disease. Abnormal lipid metabolism and intrarenal accumulation of lipids have been shown to be strongly correlated with the development and progression of diabetic kidney disease (DKD). Cholesterol, phospholipids, triglycerides, fatty acids, and sphingolipids are among the lipids that are altered in DKD, and their renal accumulation has been linked to the pathogenesis of the disease. In addition, NADPH oxidase-induced production of reactive oxygen species (ROS) plays a critical role in the development of DKD. Several types of lipids have been found to be tightly linked to NADPH oxidase-induced ROS production. This review aims to explore the interplay between lipids and NADPH oxidases in order to provide new insights into the pathogenesis of DKD and identify more effective targeted therapies for the disease.

SGLT2 Inhibitor-Dapagliflozin Attenuates Diabetes-Induced Renal Injury by Regulating Inflammation through a CYP4A/20-HETE Signaling Mechanism.

Diabetic kidney disease (DKD) is a serious complication of diabetes, affecting millions of people worldwide. Inflammation and oxidative stress are key contributors to the development and progression of DKD, making them potential targets for therapeutic interventions. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a promising class of drugs, with evidence demonstrating that they can improve renal outcomes in people with diabetes. However, the exact mechanism by which SGLT2i exert their renoprotective effects is not yet fully understood. This study demonstrates that dapagliflozin treatment attenuates renal injury observed in type 2 diabetic mice. This is evidenced by the reduction in renal hypertrophy and proteinuria. Furthermore, dapagliflozin decreases tubulointerstitial fibrosis and glomerulosclerosis by mitigating the generation of reactive oxygen species and inflammation, which are activated through the production of CYP4A-induced 20-HETE. Our findings provide insights onto a novel mechanistic pathway by which SGLT2i exerts their renoprotective effects. Overall, and to our knowledge, the study provides critical insights into the pathophysiology of DKD and represents an important step towards improving outcomes for people with this devastating condition.

Urinary 20-HETE: A prospective Non-Invasive prognostic and diagnostic marker for diabetic kidney disease.

INTRODUCTION: The identification and validation of a non-invasive prognostic marker for early detection of diabetic kidney disease (DKD) can lead to substantial improvement in therapeutic decision-making. OBJECTIVES: The main objective of this study is to assess the potential role of the arachidonic acid (AA) metabolite 20-hydroxyeicosatetraenoic (20-HETE) in predicting the incidence and progression of DKD. METHODS: Healthy patients and patients with diabetes were recruited from the Hamad General Hospital in Qatar, and urinary 20-HETE levels were measured. Data analysis was done using the Statistical Package for Social Sciences (SPSS). RESULTS: Our results show that urinary 20-HETE-to-creatinine (20-HETE/Cr) ratios were significantly elevated in patients with DKD when compared to patients with diabetes who did not exhibit clinical signs of kidney injury (p < 0.001). This correlation was preserved in the multivariate linear regression accounting for age, diabetes, family history of kidney disease, hypertension, dyslipidemia, stroke and metabolic syndrome. Urinary 20-HETE/Cr ratios were also positively correlated with the severity of kidney injury as indicated by albuminuria levels (p < 0.001). A urinary 20-HETE/Cr ratio of 4.6 pmol/mg discriminated between the presence and absence of kidney disease with a sensitivity of 82.2 % and a specificity of 67.1%. More importantly, a 10-unit increase in urinary 20-HETE/Cr ratio was tied to a 10-fold increase in the risk of developing DKD, suggesting a 20-HETE prognostic efficiency. CONCLUSION: Taken together, our results suggest that urinary 20-HETE levels can potentially be used as non-invasive diagnostic and prognostic markers for DKD.

VEGF-A: A Novel Mechanistic Link Between CYP2C-Derived EETs and Nox4 in Diabetic Kidney Disease.

Diabetes is associated with decreased epoxyeicosatrienoic acid (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of the VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the cross talk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti-VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of the VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced reactive oxygen species production. These findings were replicated in vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4. ARTICLE HIGHLIGHTS: Diabetes is associated with an alteration in cytochrome P450 2C11 (CYP2C11)-derived epoxyeicosatrienoic acid (EET) bioavailability. Decreased CYP2C11-derived EET bioavailability mediates hyperglycemia-induced glomerular injury. Decreased CYP2C11-derived EET bioavailability is associated with increased reactive oxygen species production, NADPH oxidase activity, and Nox4 expression in type 1 diabetes. Decreased CYP2C11-derived EET formation mediates hyperglycemia-induced glomerular injury through the activation of the vascular endothelial growth factor A (VEGF-A) signaling pathway. Inhibiting VEGF signaling using anti-VEGF or SU5416 attenuates type 1 diabetes-induced glomerular injury by decreasing NADPH oxidase activity and NOX4 expression.

Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes.

Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome-wide methylation patterns are poorly defined. While methylation is known to alter gene expression, the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n = 39) that was subsequently replicated in a larger validation cohort (n = 296). Gene body-related regions made up more than 60% of the methylation differences and emphasized the importance of methylation sequencing. We observed differentially methylated genes associated with DN in 3 independent T1D registries originating from Denmark (n = 445), Hong Kong (n = 107), and Thailand (n = 130). Reduced DNA methylation at CTCF and Pol2B sites was tightly connected with DN pathways that include insulin signaling, lipid metabolism, and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubule cells. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding, and the activation of insulin-signaling phosphoproteins in hyperglycemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophages and vascular endothelial cells.

Reno-Protective Effect of GLP-1 Receptor Agonists in Type1 Diabetes: Dual Action on TRPC6 and NADPH Oxidases.

Diabetic kidney disease (DKD), a serious diabetic complication, results in podocyte loss and proteinuria through NADPH oxidases (NOX)-mediated ROS production. DUOX1 and 2 are NOX enzymes that require calcium for their activation which enters renal cells through the pivotal TRPC channels. Hypoglycemic drugs such as liraglutide can interfere with this deleterious mechanism imparting reno-protection. Herein, we aim to investigate the reno-protective effect of GLP1 receptor agonist (GLP1-RA), via its effect on TRPC6 and NADPH oxidases. To achieve our aim, control or STZ-induced T1DM Sprague-Dawley rats were used. Rats were treated with liraglutide, metformin, or their combination. Functional, histological, and molecular parameters of the kidneys were assessed. Our results show that treatment with liraglutide, metformin or their combination ameliorates DKD by rectifying renal function tests and protecting against fibrosis paralleled by restored mRNA levels of nephrin, DUOX1 and 2, and reduced ROS production. Treatment with liraglutide reduces TRPC6 expression, while metformin treatment shows no effect. Furthermore, TRPC6 was found to be directly interacting with nephrin, and indirectly interacting with DUOX1, DUOX2 and GLP1-R. Our findings suggest that treatment with liraglutide may prevent the progression of diabetic nephropathy by modulating the crosstalk between TRPC6 and NADPH oxidases.

NETosis contributes to the pathogenesis of diabetes and its complications.

NETosis, a novel form of neutrophil-related cell death, acts as a major regulator of diabetes and diabetes-associated complications. In this review, we show that the extrusion of neutrophil extracellular traps, termed NETs, plays an important role in the pathogenesis of type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and diabetes-induced complications. In T1DM, ß-cell death induces the sequestration of neutrophils in the pancreas and seems to be correlated with increased NETosis. In T2DM patients, products of NETs release are significantly elevated. Increased levels of dsDNA are correlated with the presence of cardiovascular disease and diabetic kidney disease, further supporting the role of NETosis in the pathogenesis of other diabetes-induced complications such as impaired wound healing and diabetic retinopathy. NETosis is induced by high glucose through incompletely understood mechanisms, but it also appears to be elevated in patients with diabetes who have tightly controlled glucose levels. We hypothesize that hyperglycemia worsens the already elevated baseline of NETosis in diabetic patients to further increase its detrimental effects.

Prescription Errors with Chemotherapy: Quality Improvement through Standardized Order Templates.

BACKGROUND: Despite the existence of established guidelines advocating the use and value of chemotherapy order templates, chemotherapy orders are still handwritten in many hospitals in Lebanon. This manuscript describes the implementation of standardized chemotherapy order templates (COT) in a Lebanese tertiary teaching hospital through multiple steps. INITIAL ASSESSMENT: An initial assessment was conducted through a retrospective appraisal of completeness of handwritten chemotherapy orders for 100 adult patients to serve as a baseline for the project and identify parameters that might afford improvement. CHOICE OF SOLUTION: Development of over 300 standardized pre-printed COTs based on the National Comprehensive Cancer Network templates and adapted to the practice culture and patient population. IMPLEMENTATION: The COTs were implemented, using Kotter's 8-step model for leading change, by engaging health care providers, and identifying and removing barriers. EVALUATION: Assessment of physicians' compliance with the new practice (122 orders assessed) was completed through two phases and allowed for the identification of areas of improvement. LESSONS LEARNED: Overall, COT implementation showed an average improvement in order completion from 49.5% (handwritten orders) to 77.6% (phase 1-COT) to 87.6% (phase 2-COT) reflecting an increase of 38.1% between baseline and phase 2 and demonstrating that chemotherapy orders completeness was improved by pre-printed COT. As many of the hospitals in Lebanon are moving towards standardized COTs and computerized physician order entry (CPOE) in the next few years, this study provides a prototype for the successful implementation of COT and demonstrates their role in promoting quality improvement of cancer care.