ABSTRACT
Hypersensitivity reactions to ethylene oxide-sterilized dialyzers have been well described. Although ethylene oxide is no longer used to sterilize most dialyzers, it is used on other pieces of dialysis equipment. We present a case of a 78-year-old man who experienced dialysis-related anaphylaxis attributed to an IgE-mediated allergy to dialysis tubing and needles sterilized with ethylene oxide. Shortly after transitioning from a tunneled catheter to an arteriovenous fistula, he developed multiple episodes of intradialytic hypotension and syncope within minutes of starting dialysis. Laboratory evaluation revealed marked leukocytosis, eosinophilia, and elevated anti-ethylene oxide IgE antibody. After pretreatment with corticosteroids and antihistamines, the rinsing of dialysis tubing, and transition of access back to a tunneled catheter, he tolerated subsequent dialysis treatments. Review of his history revealed chronic eosinophilia since the time of hemodialysis initiation. We hypothesize his eosinophilia and mast cell degranulation began upon initial exposure to ethylene oxide and hemodialysis equipment. When use of the arteriovenous fistula was resumed, he was exposed to a higher "dose" of ethylene oxide due to the use of needles. The higher antigenic stimuli triggered a memory immune response, leading to mast cell degranulation and repeated anaphylactic episodes that were overcome by minimization of ethylene oxide-sterilized equipment, corticosteroid pretreatment, and the anti-IgE Fc monoclonal omalizumab.
Subject(s)
Anaphylaxis , Eosinophilia , Male , Humans , Aged , Renal Dialysis/adverse effects , Anaphylaxis/etiology , Needles/adverse effects , Ethylene Oxide/adverse effects , Immunoglobulin E , Eosinophilia/complications , OxidesABSTRACT
Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique with proven efficacy in a variety of conditions, including in the intensive care setting. It is not uncommon for a critically ill patient to require more than one extracorporeal procedure in addition to TPE. This review focuses on the combination of TPE with other extracorporeal circuits in a critical care setting via a single vascular access (either in-series, parallel, or a hybrid mode) which is often referred to as performing procedures "in tandem." Authors performed literature review via pubmed.gov using search terms: plasma exchange, plasmapheresis, apheresis, tandem circuits, combined circuits, critical care, ICU, CRRT, hemodialysis, and ECMO. Thirty-eight English-language, peer-reviewed papers were appraised that satisfied the content of this review on techniques for combining circuits with plasma exchange, as well as describing the advantages of tandem procedures and potential complications that can arise. Performing these procedures simultaneously can be advantageous in reducing total procedure and staffing time, avoiding placement of additional central lines, reducing overall need for anticoagulation, and limiting multiple blood primes in certain populations. However, the described combined circuits are complex, associated with higher complications, and require a skilled team to understand and mitigate the potential complications associated with these combined procedures.
Subject(s)
Extracorporeal Membrane Oxygenation , Plasma Exchange , Humans , Plasma Exchange/methods , Intensive Care Units , Renal Dialysis , Combined Modality Therapy , Retrospective StudiesABSTRACT
Sickle cell disease (SCD) is associated with significant morbidity and mortality, and limits both the quality and quantity of life. Transfusion therapy, specifically automated red cell exchange (aRCE), plays a key role in management of SCD and is beneficial for certain indications in the chronic, outpatient setting. The approach to maintain a successful chronic aRCE program for SCD is multifaceted. This review will highlight important considerations including indications for aRCE, patient selection, transfusion medicine pearls, vascular access needs, complications of therapy, aRCE prescription, and therapy optimization. Moreover, the importance of a multidisciplinary approach with frequent communication between the services involved cannot be overstated. Ultimately, the underlying goal of a chronic RCE program is to improve the quality of life and longevity of patients with SCD.
Subject(s)
Anemia, Sickle Cell , Graft vs Host Disease , Anemia, Sickle Cell/therapy , Erythrocyte Transfusion , Humans , Quality of LifeABSTRACT
OBJECTIVES: Chronic graft versus host disease (chronic GVHD) still remains the leading cause of late morbidity and mortality for allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. In this retrospective study, 53 consecutive allo-HSCT patients with chronic GVHD refractory to corticosteroids were treated with extracorporeal photopheresis (ECP). METHODS: This study was performed as a retrospective single-center study. Medical records of a total of 59 patients treated with ECP for chronic GVHD were reviewed. RESULTS: Best organ responses to ECP were observed in skin, mouth mucosa, eyes and liver. Overall response rate (ORR) to ECP was 81.2% (CR 17% and PR 64.2%). Overall survival (OS) was 84.9% and 36.7%, at 1 and 3 years, respectively. Female sex appears to have an advantage on ORR. Patients achieving ORR were able to maintain their responses with a prolonged continuation of treatments for +6 and +12 months indicating the benefits of longer ECP treatment. DISCUSSION: We found that patients with chronic GVHD who were treated with ECP for 12 months or longer had a higher response rate. Our findings in line with the data reported previously suggest that patients responding to ECP should continue longer therapy schedules to achieve a better and sustained response. In our cohort, long-term ECP therapy was safe and well-tolerated with no significant adverse effects. Best responses were observed in the patients with skin, eye, liver and oral involvement. The ECP procedure offers the advantage relative to the problems with typical immunosuppressive agents. The female sex appeared to have an advantage based on the cumulative probability of the OR after ECP for chronic GVHD.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Photopheresis , Chronic Disease , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Photopheresis/adverse effects , Photopheresis/methods , Retrospective Studies , Transplantation, Homologous/adverse effectsABSTRACT
PURPOSE OF REVIEW: Hypertension (htn) is a polygenic disorder that effects up to one third of the US population. The endoplasmic reticulum (ER) stress response is a homeostatic pathway that regulates membrane structure, protein folding, and secretory function. Emerging evidence suggests that ER stress may induce endothelial dysfunction; however, it is unclear whether ER stress-associated endothelial dysfunction modulates htn. RECENT FINDINGS: Exogenous and endogenous molecules activate ER stress in the endothelium, and ER stress mediates some forms of neurogenic htn, such as angiotensin II-dependent htn. Human studies suggest that ER stress induces endothelial dysfunction, though direct evidence that ER stress augments blood pressure in humans is lacking. However, animal and cellular models demonstrate direct evidence that ER stress influences htn. ER stress is likely one of many players in a complex interplay among molecular pathways that influence the expression of htn. Targeted activation of specific ER stress pathways may provide novel therapeutic opportunities.
Subject(s)
Endoplasmic Reticulum Stress/physiology , Endothelium, Vascular/physiopathology , Hypertension/physiopathology , Angiotensin II/metabolism , Animals , Blood Pressure/genetics , Blood Pressure/physiology , Disease Models, Animal , Endoplasmic Reticulum Stress/genetics , Endothelium, Vascular/metabolism , Humans , Hypertension/genetics , Hypertension/metabolism , Vascular Diseases/genetics , Vascular Diseases/metabolism , Vascular Diseases/physiopathologyABSTRACT
Diabetic kidney disease is the leading worldwide cause of end stage kidney disease and a growing public health challenge. The diabetic kidney is exposed to many environmental stressors and each cell type has developed intricate signaling systems designed to restore optimal cellular function. The unfolded protein response (UPR) is a homeostatic pathway that regulates endoplasmic reticulum (ER) membrane structure and secretory function. Studies suggest that the UPR is activated in the diabetic kidney to restore normal ER function and viability. However, when the cell is continuously stressed in an environment that lies outside of its normal physiological range, then the UPR is known as the ER stress response. The UPR reduces protein synthesis, augments the ER folding capacity and downregulates mRNA expression of genes by multiple pathways. Aberrant activation of ER stress can also induce inflammation and cellular apoptosis, and modify signaling of protective processes such as autophagy and mTORC activation. The following review will discuss our current understanding of ER stress in the diabetic kidney and explore novel means of modulating ER stress and its interacting signaling cascades with the overall goal of identifying therapeutic strategies that will improve outcomes in diabetic nephropathy.
ABSTRACT
The endoplasmic reticulum (ER) stress response is activated in the diabetic kidney and functions to reduce ER protein accumulation and improve cellular function. We previously showed that tribbles homolog 3 (TRB3), an ER stress-associated protein, is upregulated in the diabetic kidney. Here, we investigated whether absence of TRB3 alters outcomes in diabetic nephropathy. Type 1 diabetes was induced in TRB3 wild-type and knockout ((-/-)) mice by low-dose streptozotocin, and the mice were followed for 12 weeks. Diabetic TRB3(-/-) mice developed higher levels of albuminuria and increased expression of inflammatory cytokine and chemokine mRNA in renal cortices relative to wild-type littermates, despite similar hyperglycemia. Diabetic TRB3(-/-) mice also expressed higher levels of ER stress-associated molecules in both the renal cortices and glomeruli. This change was associated with higher renal cortical phosphorylation of AKT at serine 473 (Ser(473)), which is the AKT site phosphorylated by mammalian target of rapamycin complex-2 (mTORC2). We show in renal tubular cells that TRB3 binds to mTOR and the rapamycin-insensitive companion of mTOR (Rictor), a protein specific to mTORC2. Finally, we demonstrate in murine tubular cells that TRB3 can inhibit secretion of IL-6. Thus, TRB3 reduces albuminuria and inflammatory gene expression in diabetic kidney disease by a mechanism that may involve inhibition of the mTORC2/AKT pathway and may prove to be a novel therapeutic target.
Subject(s)
Cell Cycle Proteins/metabolism , Diabetic Nephropathies/metabolism , Multiprotein Complexes/metabolism , TOR Serine-Threonine Kinases/metabolism , Albuminuria/etiology , Albuminuria/genetics , Albuminuria/metabolism , Animals , Carrier Proteins/metabolism , Cell Cycle Proteins/deficiency , Cell Cycle Proteins/genetics , Diabetic Nephropathies/genetics , Diabetic Nephropathies/pathology , Endoplasmic Reticulum Stress , Gene Expression , Inflammation/genetics , Inflammation/metabolism , Interleukin-6/genetics , Kidney/metabolism , Kidney/pathology , Male , Mechanistic Target of Rapamycin Complex 2 , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation , Protein Binding , Proto-Oncogene Proteins c-akt/chemistry , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rapamycin-Insensitive Companion of mTOR Protein , Serine/chemistry , Signal TransductionABSTRACT
BACKGROUND: To enhance donor availability, almost half of hematopoietic progenitor cell transplants (HPCTs) cross ABO blood type boundaries. ABO-incompatible HPCTs are well tolerated; however, there is an increased risk of delayed hemolysis in patients with minor and bidirectional ABO mismatches. Delayed hemolysis generally occurs 1 to 2 weeks after HPCT and is related to production of alloantibodies directed against recipient ABO red blood cell (RBC) antigens by passenger donor lymphocytes. One previous study has suggested that prophylactic RBC exchange in patients with minor and bidirectional ABO-mismatched HPCT reduces the risks of severe immune hemolysis, but this recommendation is controversial. STUDY DESIGN AND METHODS: Herein we describe our experience using prophylactic RBC exchange in patients with minor and bidirectional ABO-mismatched HPCTs who were deemed to be at high risk for immune hemolysis. We compare the group of patients that received prophylactic RBC exchange with a historical cohort of ABO-mismatched patients who underwent HPCT without prophylactic RBC exchange. RESULTS: Our study suggests that prophylactic RBC exchange in minor and bidirectional ABO-mismatched HPCT does not reduce severe immune hemolysis, nor does it improve 1-year survival, the number of RBC units transfused after transplant, or length of hospitalization after HPCT. CONCLUSION: This study failed to identify a clear role for selected prophylactic RBC exchange in patients who were deemed at risk for severe post-HPCT immune hemolysis.
Subject(s)
ABO Blood-Group System/immunology , Blood Group Incompatibility/immunology , Erythrocyte Transfusion/methods , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation Conditioning/methods , Adult , Aged , Blood Group Incompatibility/complications , Case-Control Studies , Cohort Studies , Female , Graft vs Host Disease/immunology , Hemolysis , Humans , Male , Middle Aged , Transplantation Conditioning/adverse effectsABSTRACT
Selective apheresis procedures have been developed to target specific molecules, antibodies, or cellular elements in a variety of diseases. The advantage of the selective apheresis procedures over conventional therapeutic plasmapheresis is preservation of other essential plasma components such as albumin, immunoglobulins, and clotting factors. These procedures are more commonly employed in Europe and Japan, and few are available in the USA. Apheresis procedures discussed in this review include the various technologies available for low-density lipoprotein (LDL) apheresis, double filtration plasmapheresis (DFPP), cryofiltration, immunoadsorption procedures, adsorption resins that process plasma, extracorporeal photopheresis, and leukocyte apheresis.
Subject(s)
Blood Component Removal/methods , Autoantibodies/blood , Blood Cells , Blood Component Removal/instrumentation , Cryoglobulins , Filtration/instrumentation , Filtration/methods , Humans , Immobilized Proteins , Immunoglobulins/blood , Immunosorbent Techniques/instrumentation , Lipids/blood , Lipoproteins/blood , Photopheresis/instrumentation , Photopheresis/methods , Resins, Synthetic , Staphylococcal Protein A , United StatesABSTRACT
In 2000, investigators discovered Tribbles, a Drosophila protein that coordinates morphogenesis by inhibiting mitosis. Further work has delineated Xenopus (Xtrb2), Nematode (Nipi-3), and mammalian homologs of Drosophila tribbles, which include TRB1, TRB2, and TRB3. The sequences of tribbles homologs are highly conserved, and despite their protein kinase structure, to date they have not been shown to have kinase activity. TRB family members play a role in the differentiation of macrophages, lymphocytes, muscle cells, adipocytes, and osteoblasts. TRB isoforms also coordinate a number of critical cellular processes including glucose and lipid metabolism, inflammation, cellular stress, survival, apoptosis, and tumorigenesis. TRB family members modulate multiple complex signaling networks including mitogen activated protein kinase cascades, protein kinase B/AKT signaling, mammalian target of rapamycin, and inflammatory pathways. The following review will discuss metazoan homologs of Drosophila tribbles, their structure, expression patterns, and functions. In particular, we will focus on TRB3 function in the kidney in podocytes. This review will also discuss the key signaling pathways with which tribbles proteins interact and provide a rationale for developing novel therapeutics that exploit these interactions to provide better treatment options for both acute and chronic kidney disease.
ABSTRACT
The Na-glucose cotransporter SGLT2 mediates high-capacity glucose uptake in the early proximal tubule and SGLT2 inhibitors are developed as new antidiabetic drugs. We used gene-targeted Sglt2 knockout (Sglt2(-/-)) mice to elucidate the contribution of SGLT2 to blood glucose control, glomerular hyperfiltration, kidney growth, and markers of renal growth and injury at 5 wk and 4.5 mo after induction of low-dose streptozotocin (STZ) diabetes. The absence of SGLT2 did not affect renal mRNA expression of glucose transporters SGLT1, NaGLT1, GLUT1, or GLUT2 in response to STZ. Application of STZ increased blood glucose levels to a lesser extent in Sglt2(-/-) vs. wild-type (WT) mice (â¼300 vs. 470 mg/dl) but increased glucosuria and food and fluid intake to similar levels in both genotypes. Lack of SGLT2 prevented STZ-induced glomerular hyperfiltration but not the increase in kidney weight. Knockout of SGLT2 attenuated the STZ-induced renal accumulation of p62/sequestosome, an indicator of impaired autophagy, but did not attenuate the rise in renal expression of markers of kidney growth (p27 and proliferating cell nuclear antigen), oxidative stress (NADPH oxidases 2 and 4 and heme oxygenase-1), inflammation (interleukin-6 and monocyte chemoattractant protein-1), fibrosis (fibronectin and Sirius red-sensitive tubulointerstitial collagen accumulation), or injury (renal/urinary neutrophil gelatinase-associated lipocalin). SGLT2 deficiency did not induce ascending urinary tract infection in nondiabetic or diabetic mice. The results indicate that SGLT2 is a determinant of hyperglycemia and glomerular hyperfiltration in STZ-induced diabetes mellitus but is not critical for the induction of renal growth and markers of renal injury, inflammation, and fibrosis.
Subject(s)
Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/metabolism , Hyperglycemia/metabolism , Kidney/growth & development , Sodium-Glucose Transporter 2/metabolism , Animals , Blood Glucose , Diabetes Mellitus, Experimental/blood , Diabetic Nephropathies/genetics , Glomerular Filtration Rate , Hyperglycemia/blood , Kidney/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Organ Size , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Sodium-Glucose Transporter 2/geneticsABSTRACT
BACKGROUND/AIMS: Acute kidney injury (AKI) contributes to significant morbidity and mortality in the intensive care unit (ICU). Plasma levels of interleukin (IL)-6 predict the development of AKI and are associated with higher mortality in ICU patients with AKI. Most studies in AKI have focused on the tubulo-interstitium, despite evidence of glomerular involvement. In the following study, our goals were to investigate the expression of IL-6 and its downstream mediators in septic-induced AKI. METHODS: Podocytes were treated in vitro with lipopolysaccharide (LPS) and mice were treated with LPS, and we evaluated IL-6 expression by real-time PCR, ELISA and in situ RNA hybridization. RESULTS: Following LPS stimulation, IL-6 is rapidly and highly induced in cultured podocytes and in vivo in glomeruli and infiltrating leukocytes. Surprisingly, in direct response to exogenous IL-6, podocytes produce lipocalin-2/neutrophil gelatinase-associated lipocalin (Lcn2/Ngal). LPS also potently induces Lcn2/Ngal expression in podocytes in culture and in glomeruli in vivo. Intense Lcn2/Ngal expression is also observed in IL-6 knockout mice, suggesting that while IL-6 may be sufficient to induce glomerular Lcn2/Ngal expression, it is not essential. CONCLUSIONS: The glomerulus is involved in septic AKI, and we demonstrate that podocytes secrete key mediators of AKI including IL-6 and Lcn2/Ngal.
Subject(s)
Acute Kidney Injury/metabolism , Acute-Phase Proteins/biosynthesis , Interleukin-6/biosynthesis , Kidney Glomerulus/metabolism , Lipocalins/biosynthesis , Lipopolysaccharides/toxicity , Oncogene Proteins/biosynthesis , Podocytes/metabolism , Acute Kidney Injury/chemically induced , Acute Kidney Injury/pathology , Acute-Phase Proteins/metabolism , Animals , Cell Line, Transformed , Cells, Cultured , Interleukin-6/metabolism , Lipocalin-2 , Lipocalins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Oncogene Proteins/metabolism , Podocytes/drug effectsABSTRACT
Thiazolidinediones (TZDs), known as peroxisome proliferator-activated receptor (PPAR) agonists, are used to treat type 2 diabetes. However, â¼5% of patients experience the treatment-limiting side effect of edema. Studies have implicated activation of the epithelial sodium channel (ENaC) as a cause of TZD-induced fluid retention, although there have been conflicting reports. The goal of this study was to resolve the role of PPARγ in control of ENaC isoforms in the kidney. Herein, we demonstrate in mice that rosiglitazone (RGZ), a PPARγ ligand, increases body weight and abdominal fat pad fluid content and reduces hematocrit. Seven days of RGZ decreases ENaCα and ENaCß mRNA and ENaCγ protein expression in the kidney cortex, and acute treatment for 5 h with pioglitazone, another potent TZD, does not increase renal ENaC isoform mRNA or protein expression. Pioglitazone also decreases ENaCα and ENaCγ mRNA expression in a cortical collecting duct cell line. As no direct transcriptional studies had been conducted, we examined the PPARγ-dependent regulation of ENaC. Pioglitazone represses ENaCγ promoter activity, and this repression is partially relieved by inhibition of protein synthesis. Chromatin immunoprecipitation assays revealed that repression is associated with a decrease in histone H4K5 acetylation at the proximal ENaCγ promoter. In summary, TZDs do not increase ENaC mRNA expression in the kidney, and in fact repress the ENaCγ promoter via an indirect transcriptional mechanism.
Subject(s)
Epithelial Sodium Channels/metabolism , Hypoglycemic Agents/pharmacology , Kidney/drug effects , PPAR gamma/agonists , Thiazolidinediones/pharmacology , Abdominal Fat/drug effects , Acetylation , Animals , Body Weight/drug effects , Epithelial Sodium Channels/genetics , Kidney/metabolism , Mice , Pioglitazone , Promoter Regions, Genetic , RosiglitazoneABSTRACT
To clarify the physiological role of Na(+)-D-glucose cotransporter SGLT1 in small intestine and kidney, Sglt1(-/-) mice were generated and characterized phenotypically. After gavage of d-glucose, small intestinal glucose absorption across the brush-border membrane (BBM) via SGLT1 and GLUT2 were analyzed. Glucose-induced secretion of insulinotropic hormone (GIP) and glucagon-like peptide 1 (GLP-1) in wild-type and Sglt1(-/-) mice were compared. The impact of SGLT1 on renal glucose handling was investigated by micropuncture studies. It was observed that Sglt1(-/-) mice developed a glucose-galactose malabsorption syndrome but thrive normally when fed a glucose-galactose-free diet. In wild-type mice, passage of D-glucose across the intestinal BBM was predominantly mediated by SGLT1, independent the glucose load. High glucose concentrations increased the amounts of SGLT1 and GLUT2 in the BBM, and SGLT1 was required for upregulation of GLUT2. SGLT1 was located in luminal membranes of cells immunopositive for GIP and GLP-1, and Sglt1(-/-) mice exhibited reduced glucose-triggered GIP and GLP-1 levels. In the kidney, SGLT1 reabsorbed â¼3% of the filtered glucose under normoglycemic conditions. The data indicate that SGLT1 is 1) pivotal for intestinal mass absorption of d-glucose, 2) triggers the glucose-induced secretion of GIP and GLP-1, and 3) triggers the upregulation of GLUT2.
Subject(s)
Glucose/pharmacokinetics , Incretins/metabolism , Intestinal Absorption/genetics , Sodium-Glucose Transporter 1/physiology , Animals , Female , Glucose/pharmacology , Glycosuria/metabolism , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Intestine, Small/metabolism , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Oocytes/drug effects , Oocytes/metabolism , Sodium-Glucose Transporter 1/genetics , Sodium-Glucose Transporter 1/metabolismABSTRACT
The mechanisms underlying the association between obesity and progressive renal disease are not well understood. Exposure to a high-fat diet decreases levels of the cellular energy sensor AMPK in many organs, including the kidney, but whether AMPK contributes to the pathophysiology of kidney disease induced by a high-fat diet is unknown. In this study, we randomly assigned C57BL/6J mice to a standard or high-fat diet. After 1 week, mice fed a high-fat diet exhibited an increase in body weight, renal hypertrophy, an increase in urine H(2)O(2) and urine MCP-1, and a decrease in circulating adiponectin levels and renal AMPK activity. Urine ACR progressively increased after 4 weeks of a high-fat diet. After 12 weeks, kidneys of mice fed a high-fat diet demonstrated a marked increase in markers of fibrosis and inflammation, and AMPK activity remained significantly suppressed. To determine whether inhibition of AMPK activity explained these renal effects, we administered an AMPK activator along with a high-fat diet for 1 week. Although AMPK activation did not abrogate the weight gain, it reduced the renal hypertrophy, urine H(2)O(2), and urine and renal MCP-1. In vitro, AMPK activation completely inhibited the induction of MCP-1 by palmitic acid in mesangial cells. In conclusion, these data suggest that the energy sensor AMPK mediates the early renal effects of a high-fat diet.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Dietary Fats/adverse effects , Kidney Diseases/metabolism , Obesity/enzymology , Albuminuria/etiology , Animals , Biomarkers/urine , Chemokine CCL2/metabolism , Diet, High-Fat/adverse effects , Enzyme Activation , Hyperglycemia/etiology , Hypertrophy/etiology , Insulin Resistance , Kidney Diseases/etiology , Kidney Diseases/pathology , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Mice , Mice, Inbred C57BL , Obesity/complicationsABSTRACT
Diabetic nephropathy (DN) is clinically characterized by proteinuria and hypertension. Investigations suggest that matrix accumulation and inflammatory processes contribute to the pathological features of this progressive disease. This chapter reviews novel targeted approaches to the treatment of DN, with the goal of slowing the progression and improving renal function. Many studies support the use of agents that block the renin-angiotensin-aldosterone system in DN. Novel, oral agents that are promising in early clinical studies are agents such as pirfenidone and bardoxolone as they are associated with early improvement in renal function in patients with advanced diabetic kidney disease. Additionally, strategies that inhibit inflammatory cytokines, chemokines, adhesion molecules and mediators of the innate immune response may provide novel targets for the treatment of DN. Larger clinical studies are eagerly awaited to determine if new agents that specifically block kidney fibrosis and inflammation will delay, arrest and possibly reverse progressive renal failure.
Subject(s)
Diabetic Nephropathies/drug therapy , Animals , Connective Tissue Growth Factor/antagonists & inhibitors , Fibrosis/prevention & control , Glycation End Products, Advanced/antagonists & inhibitors , Humans , Kidney/pathology , Renin-Angiotensin System/physiology , Transforming Growth Factor beta/antagonists & inhibitorsABSTRACT
The endoplasmic reticulum (ER) folds and modifies proteins; however, during conditions of cellular stress, unfolded proteins accumulate in the ER and activate the unfolded protein response (UPR). The UPR, also referred to as the ER stress response, activates three distinct signaling cascades that are designed to globally reduce transcription and translation. The three major arms of the mammalian UPR include 1) protein kinase RNA (PKR)-like ER kinase (PERK), 2) inositol-requiring protein-1 (IRE1α), and 3) activating transcription factor-6 (ATF6) pathways. The PERK pathway rapidly attenuates protein translation, whereas the ATF6 and IRE1α cascades transcriptionally upregulate ER chaperone genes that promote proper folding and ER-associated degradation (ERAD) of proteins. This integrated response in turn allows the folding machinery of the ER to catch up with the backlog of unfolded proteins. The ER stress response plays a role in a number of pathophysiological processes, including pancreatic ß-cell failure and apoptosis. The goals of the current review are to familiarize investigators with cellular and tissue activation of this response in the rodent and human diabetic kidney. Additionally, we will review therapeutic modulators of the ER stress response and discuss their efficacy in models of diabetic kidney disease. The ER stress response has both protective and deleterious features. A better understanding of the molecular pathways regulated during this process in a cell- and disease-specific manner could reveal novel therapeutic strategies in chronic renal diseases, including diabetic kidney disease.
Subject(s)
Diabetic Nephropathies/metabolism , Endoplasmic Reticulum/metabolism , Kidney/metabolism , Stress, Physiological , Unfolded Protein Response , Animals , Cytoprotection , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/physiopathology , Endoplasmic Reticulum/drug effects , Humans , Kidney/drug effects , Kidney/physiopathology , Signal TransductionABSTRACT
Mutations in the gene encoding for the Na(+)-glucose co-transporter SGLT2 (SLC5A2) associate with familial renal glucosuria, but the role of SGLT2 in the kidney is incompletely understood. Here, we determined the localization of SGLT2 in the mouse kidney and generated and characterized SGLT2-deficient mice. In wild-type (WT) mice, immunohistochemistry localized SGLT2 to the brush border membrane of the early proximal tubule. Sglt2(-/-) mice had glucosuria, polyuria, and increased food and fluid intake without differences in plasma glucose concentrations, GFR, or urinary excretion of other proximal tubular substrates (including amino acids) compared with WT mice. SGLT2 deficiency did not associate with volume depletion, suggested by similar body weight, BP, and hematocrit; however, plasma renin concentrations were modestly higher and plasma aldosterone levels were lower in Sglt2(-/-) mice. Whole-kidney clearance studies showed that fractional glucose reabsorption was significantly lower in Sglt2(-/-) mice compared with WT mice and varied in Sglt2(-/-) mice between 10 and 60%, inversely with the amount of filtered glucose. Free-flow micropuncture revealed that for early proximal collections, 78 ± 6% of the filtered glucose was reabsorbed in WT mice compared with no reabsorption in Sglt2(-/-) mice. For late proximal collections, fractional glucose reabsorption was 93 ± 1% in WT and 21 ± 6% in Sglt2(-/-) mice, respectively. These results demonstrate that SGLT2 mediates glucose reabsorption in the early proximal tubule and most of the glucose reabsorption by the kidney, overall. This mouse model mimics and explains the glucosuric phenotype of individuals carrying SLC5A2 mutations.
Subject(s)
Glucose/metabolism , Kidney Tubules, Proximal/metabolism , Sodium-Glucose Transporter 2/metabolism , Absorption/physiology , Aldosterone/blood , Animals , Disease Models, Animal , Mice , Mice, Knockout , Microvilli/metabolism , RNA, Messenger/metabolism , Renin/blood , Sodium-Glucose Transporter 2/geneticsABSTRACT
The prevalence of diabetic nephropathy continues to rise, highlighting the importance of investigating and discovering novel treatment strategies. TRB3 is a kinase-like molecule that modifies cellular survival and metabolism and interferes with signal transduction pathways. Herein, we report that TRB3 expression is increased in the kidneys of type 1 and type 2 diabetic mice. TRB3 is expressed in conditionally immortalized podocytes; however, it is not stimulated by elevated glucose. The diabetic milieu is associated with increased oxidative stress and circulating free fatty acids (FFA). We show that reactive oxygen species (ROS) such as H(2)O(2) and superoxide anion (via the xanthine/xanthine oxidase reaction) as well as the FFA palmitate augment TRB3 expression in podocytes. C/EBP homologous protein (CHOP) is a transcription factor that is associated with the endoplasmic reticulum stress response. CHOP expression increases in diabetic mouse kidneys and in podocytes treated with ROS and FFA. In podocytes, transfection of CHOP increases TRB3 expression, and ROS augment recruitment of CHOP to the proximal TRB3 promoter. MCP-1/CCL2 is a chemokine that contributes to the inflammatory injury associated with diabetic nephropathy. In these studies, we demonstrate that TRB3 can inhibit basal and stimulated podocyte production of MCP-1. In summary, enhanced ROS and/or FFA associated with the diabetic milieu induce podocyte CHOP and TRB3 expression. Because TRB3 inhibits MCP-1, manipulation of TRB3 expression could provide a novel therapeutic approach in diabetic kidney disease.
Subject(s)
Cell Cycle Proteins/biosynthesis , Chemokine CCL2/antagonists & inhibitors , Diabetic Nephropathies/metabolism , Endoplasmic Reticulum/metabolism , Podocytes/metabolism , Transcription Factor CHOP/metabolism , Animals , Blotting, Western , Cell Cycle Proteins/genetics , Cell Cycle Proteins/pharmacology , Chemokine CCL2/biosynthesis , Chromatin/metabolism , DNA/biosynthesis , DNA/genetics , Diabetes Mellitus, Experimental/metabolism , Fluorescent Antibody Technique , Immunoprecipitation , Kidney/cytology , Kidney/metabolism , Male , Mice , Mice, Inbred C57BL , Palmitates/metabolism , Plasmids/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Reactive Oxygen Species/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Up-Regulation/drug effectsABSTRACT
PPARalpha ligands are medications used clinically to prevent cardiovascular events, however studies have shown that these agents are also anti-inflammatory. Our previous studies have shown that PPARalpha ligands induce lymphocyte depletion. PPARalpha ligands also potently upregulate TRB3, a protein that has been associated with cell cycle arrest. Therefore the following studies were undertaken to determine the mechanisms associated with lymphocyte depletion. Our studies demonstrate that WY14,643, a PPARalpha ligand, decreases the amount of lymphocytes recovered after stimulation and reduces cellular divisions. Cells treated with WY14,643 also accumulate in the G2/S phase of the cell cycle. TRB3 has been shown to inhibit the phosphorylation of AKT/Protein Kinase B, and reduced activation of AKT has been associated with decreased cellular divisions and survival. However in lymphocytes, TRB3 did not reduce the phosphorylation of AKT, and WY14,643 treatment was associated with enhanced activation of AKT. Drosophila tribbles (TRB3 homolog) causes G2 arrest by decreasing the expression of a Cdc25c homolog. Lymphocytes stimulated and treated with WY14,643 have reduced expression of Cdc25c, however this is not associated with enhanced expression of phosphorylated-Cdc2 which induces G2 arrest. Instead we observed that WY14,643 consistently reduces the protein and mRNA expression of Cyclin B1. Moreover, TRB3 inhibits activation of a Cyclin B1 promoter construct. In summary, we propose that PPARalpha ligands may reduce cellular number by augmenting TRB3 expression, which in turn induces cell cycle arrest by reducing the expression of Cyclin B1. Reduced cellular divisions and cell cycle arrest may be responsible for some of the immunomodulatory effects of these agents that have been consistently observed in human trials.