High levels of glucose induce epithelial-mesenchymal transition in renal proximal tubular cells through PERK-eIF2a pathway

Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure worldwide, affecting up to 40% of people with diabetes. While glomerular damage (like mesangial expansion) is well-known in DKD, growing evidence shows tubulointerstitial fibrosis—scarring in the kidney’s tubules and surrounding tissue—is equally critical to progressive kidney loss. A key driver of this fibrosis? Epithelial-mesenchymal transition (EMT), where kidney tubular cells lose their normal structure and transform into myofibroblasts—the cells that produce scar tissue.

But how does high blood glucose (hyperglycemia), the root of diabetes, trigger EMT in kidney cells? A 2019 study by Yan Bao (Department of Endocrinology, Renmin Hospital of Wuhan University) and colleagues sheds light on this question, linking high glucose to EMT via a stress response in the cell’s endoplasmic reticulum (ER).

What Is EMT, and Why Does It Matter for Kidneys?

EMT is a process where epithelial cells (like those lining kidney tubules) take on mesenchymal (fibroblast-like) traits. For kidneys, this means tubular cells stop functioning as filters and start producing α-smooth muscle actin (α-SMA)—a protein marker of myofibroblasts and a red flag for fibrosis. The more α-SMA, the more scarring—and the faster kidney function declines.

ER Stress: The Hidden Link Between High Glucose and EMT

The ER is a cellular “factory” that folds proteins into their functional shapes. When stressors like high glucose, hypoxia, or inflammation overload the ER, misfolded proteins build up—a condition called ER stress. To fix this, cells activate the unfolded protein response (UPR), a set of pathways that either restore balance or trigger cell death if stress is too severe.

One key UPR pathway involves PERK (protein kinase R-like ER kinase), a protein that binds to the chaperone GRP78 (a marker of ER stress) under normal conditions. When ER stress hits, PERK detaches from GRP78, activates itself, and phosphorylates (turns on) eIF2α—a protein that slows protein production to reduce ER overload.

But in diabetes, chronic high glucose keeps the ER in a state of constant stress. Bao and team hypothesized this overactive PERK-eIF2α pathway might drive EMT in kidney cells.

The Study: How High Glucose Triggers EMT via PERK-eIF2a

The researchers used NRK-52E cells—a lab model of rat renal proximal tubular cells—to test their theory. Here’s what they did:

High glucose treatments: Cells were exposed to normal glucose (5.6 mmol/L, “NC group”) or high glucose (15, 25, or 50 mmol/L) for 24–48 hours. A “mannitol group” (normal glucose + mannitol, to mimic high osmosis without glucose) served as a control.
ER stress induction: Cells were treated with thapsigargin—a drug that intentionally causes ER stress—to see if it alone could trigger EMT.
PERK inhibition: Cells were pre-treated with GSK2606414—a selective PERK inhibitor—to block the PERK-eIF2α pathway and measure its effect on EMT.

The team used Western blot analysis to track:

α-SMA (EMT marker)
GRP78 (ER stress marker)
Phosphorylated PERK (p-PERK) and phosphorylated eIF2α (p-eIF2α, signs of pathway activation)

Key Results: High Glucose Activates ER Stress and EMT—via PERK-eIF2a

The data painted a clear picture:

1. High glucose increases α-SMA (EMT) in a dose- and time-dependent way

Compared to normal glucose, high glucose (15–50 mmol/L) raised α-SMA levels by 90–152% after 48 hours.
Longer exposure (48 vs. 24 hours) to high glucose (25 mmol/L) doubled α-SMA levels.
Mannitol (osmosis control) had no effect—so the EMT wasn’t due to high osmosis, just high glucose.

2. High glucose triggers ER stress (and PERK-eIF2a activation)

High glucose increased GRP78 (ER stress marker) by 30–58% and boosted p-PERK (PERK activation) by 51–79% (peaking at 25 mmol/L glucose).
p-eIF2α (eIF2α activation) rose by 27–70% with high glucose.
Total PERK and eIF2α levels stayed the same—meaning the pathway was activated, not overproduced.

3. ER stress alone causes EMT, and PERK inhibition blocks it

Thapsigargin (ER stress inducer) increased α-SMA by 129–186% (highest at 0.1 µmol/L for 24 hours).
Pre-treating cells with GSK2606414 (PERK inhibitor) cut thapsigargin-induced α-SMA by 34%—proving the PERK-eIF2α pathway is key to ER stress-driven EMT.

4. PERK inhibition blocks high glucose-induced EMT

GSK2606414 (100 nmol/L) reduced high glucose-induced p-eIF2α by 40% and α-SMA by 34%.

What This Means for Diabetic Kidney Disease

Bao and colleagues’ work fills a critical gap in DKD research: it links chronic high glucose to kidney fibrosis through ER stress and the PERK-eIF2α pathway. Here’s why this matters:

EMT is a direct driver of fibrosis: By showing high glucose triggers EMT via PERK-eIF2α, the study identifies a new target for stopping DKD progression.
ER stress is a modifiable risk: Unlike some genetic factors, ER stress can be targeted with drugs (like PERK inhibitors or ER chaperones). For example, previous research found the ER stress blocker 4-PBA reduced kidney damage in diabetic rats.
Osmosis isn’t the culprit: The mannitol control rules out high sugar’s osmotic effects—meaning the damage comes from glucose itself, not just “thick” blood.

Limitations and Next Steps

The study was done in lab cells, not living animals or humans. Future research needs to confirm these findings in diabetic mouse models and clinical trials. But the results are promising: if PERK-eIF2α is indeed a key driver of DKD fibrosis, targeting this pathway could slow or stop kidney failure in people with diabetes.

Original Study Citation

Bao Y, Ao Y, Yi B, Batubayier J. High levels of glucose induce epithelial-mesenchymal transition in renal proximal tubular cells through PERK-eIF2a pathway. Chinese Medical Journal. 2019;132(7):868–872. doi:10.1097/CM9.0000000000000157

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