Related Experiment Video
Updated: Jul 1, 2026
10:12
Measuring Endoplasmic Reticulum Stress and Unfolded Protein Response in HIV-1 Infected T-Cells and Analyzing its Role in HIV-1 Replication
Published on: June 14, 2024
Proteinuria and hyperglycemia induce endoplasmic reticulum stress
Maja T Lindenmeyer1, Maria P Rastaldi, Masami Ikehata
1Nephrology Center, Medizinische Poliklinik, University of Munich, Munich, Germany.
Journal of the American Society of Nephrology : JASN
|September 9, 2008
Summary
Diabetic nephropathy (DN) and proteinuria induce endoplasmic reticulum (ER) stress in kidney cells, activating the unfolded protein response (UPR). This adaptive UPR may protect cells, but prolonged stress can lead to apoptosis.
Area of Science:
- Nephrology
- Molecular Biology
- Cellular Biology
Background:
- The endoplasmic reticulum (ER) is crucial for protein folding.
- ER stress occurs when protein folding capacity is overwhelmed, triggering the unfolded protein response (UPR).
- Sustained UPR failure can lead to apoptosis.
Purpose of the Study:
- To investigate if proteinuria and hyperglycemia induce ER stress in renal epithelial cells.
- To analyze the association between the degree of diabetic nephropathy (DN) and UPR gene expression.
- To examine the role of ER stress in proteinuric kidney diseases.
Main Methods:
- Microarray analysis of kidney biopsies from patients with diabetic nephropathy (DN) and controls.
- Real-time reverse transcriptase-PCR to validate gene expression findings.
- Immunofluorescence staining to confirm protein upregulation in renal biopsies.
- In vitro experiments exposing renal tubular epithelial cells to albumin and high glucose.
Main Results:
- UPR gene expression was significantly different in established DN compared to mild DN or control kidneys.
- Expression of XBP1, HSPA5, and HYOU1 was increased in established DN, while DDIT3 remained unchanged.
- HSPA5 and HYOU1 protein upregulation was confirmed in tubular epithelia of DN patients.
- In vitro exposure to albumin and high glucose enhanced ER stress gene expression in renal tubular epithelial cells.
Conclusions:
- Tubular epithelial cells in proteinuric diseases experience ER stress, activating a protective UPR.
- The degree of DN correlates with UPR gene expression.
- While UPR offers protection, persistent hyperglycemia and proteinuria may ultimately cause apoptosis in renal cells.
Related Concept Videos
01:17Role of ER in the Secretory Pathway
Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
01:37The Unfolded Protein Response
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
01:31Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
01:28Diabetic Nephropathy
Definition Diabetic nephropathy is a chronic kidney complication that results from prolonged hyperglycemia.Prevalence It is the most common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide, affecting up to half of individuals with diabetes.Pathophysiology • Sustained hyperglycemia triggers multiple hemodynamic and metabolic changes in the kidney. • Early in the disease, increased renal blood flow and glomerular hyperfiltration occur due to afferent arteriolar...
01:32Export of Misfolded Proteins out of the ER
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
01:29Hyperglycemia
Hyperglycemia is an abnormally high blood glucose level. It is diagnosed by fasting glucose ≥126 mg/dL, 2-hour oral glucose tolerance test (or OGTT) ≥200 mg/dL, random glucose ≥200 mg/dL with symptoms, or HbA1c ≥6.5%. However, HbA1c results may be unreliable in certain conditions, such as anemia or hemoglobinopathies, and the diagnosis should be confirmed unless classic symptoms are present. Postprandial hyperglycemia is typically considered significant when glucose levels exceed 180 mg/dL two...