Endoplasmic Reticulum Stress in Kidney Diseases

Endoplasmic reticulum (ER) stress arises when the folding capacity of the ER is overwhelmed by misfolded or unfolded proteins. In the kidney, diverse insults such as hyperglycaemia, ischaemia–reperfusion, proteinuria and toxic injury perturb ER homeostasis in specialised cells including podocytes and tubular epithelial cells. The resulting activation of the unfolded protein response (UPR) initially aims to restore proteostasis by attenuating protein synthesis, enhancing chaperone expression and promoting ER‐associated degradation (ERAD). However, when ER stress is severe or prolonged, the UPR shifts towards pro‐apoptotic signalling, contributing to tubular cell death, glomerular dysfunction and interstitial fibrosis. Crosstalk with mitochondrial stress pathways and inflammatory cascades further amplifies tissue injury. Maintaining ER homeostasis through adaptive UPR branches, selective autophagy and interorganelle communication has emerged as a critical determinant of renal resilience. Therapeutic strategies that fine‐tune ER stress responses hold promise for slowing chronic kidney disease progression and improving outcomes in acute kidney injury.

Research from Nature Portfolio

Seminal studies have elucidated how defective ER stress signalling drives progressive renal damage. Work on diabetic nephropathy has demonstrated that impaired insulin–p85–XBP1 signalling in podocytes selectively blunts the beneficial spliced X-box binding protein 1 (XBP1) response while sustaining ATF6 and CHOP activation, thereby accelerating glomerular sclerosis. Restoration of XBP1 nuclear translocation has been proposed to rebalance adaptive versus maladaptive UPR pathways. Investigations into proteinuria‐induced tubular injury have identified albumin‐triggered cytosolic calcium elevation as a driver of ATF4‐mediated Lipocalin 2 upregulation, culminating in apoptosis and interstitial lesions; chemical chaperones such as 4-phenylbutyrate counter this cascade and preserve renal architecture. Foundational work on reticulon 1A has revealed its role as an ER membrane‐shaping protein that interacts with PERK to instigate chronic ER stress, promoting tubular cell apoptosis and fibrogenesis; silencing reticulon 1A attenuates both ER stress markers and renal fibrosis in obstructive and diabetic models.

Endoplasmic Reticulum Stress in Kidney Diseases publication trend

The graph below shows the total number of articles in endoplasmic reticulum stress in kidney diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Endoplasmic reticulum (ER) stress: Disruption of ER homeostasis leading to accumulation of misfolded proteins and activation of stress pathways.

Unfolded protein response (UPR): Adaptive signalling cascade launched by ER stress to restore protein folding capacity or induce cell death.

ER-associated degradation (ERAD): Quality‐control mechanism that disposes of misfolded ER proteins via the ubiquitin–proteasome system.

Autophagy: Lysosomal degradation pathway that clears damaged organelles and misfolded proteins to support cellular homeostasis.

Podocyte: Specialised glomerular epithelial cell essential for maintaining the filtration barrier.

Proteinuria: Abnormal leakage of plasma proteins into urine indicative of glomerular or tubular injury.

References

1. Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury. International Journal of Biological Sciences (2024).
2. Research progress on endoplasmic reticulum homeostasis in kidney diseases. Cell Death & Disease (2023).
3. XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury. Cell Death Discovery (2023).
4. Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nature Communications (2015).
5. Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2. Nature Communications (2016).
6. RTN1 mediates progression of kidney disease by inducing ER stress. Nature Communications (2015).