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Kidney Week

Abstract: TH-PO482

Diabetic Glomeruli Stiffen as They Scar

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Ulloa severino, Luisa, St. Michael''s Hospital Keenan Research Centre for Biomedical Science, Toronto, Ontario, Canada
  • He, Xiaolin, St. Michael''s Hospital Keenan Research Centre for Biomedical Science, Toronto, Ontario, Canada
  • Poloni, Laura N., University of Toronto, Toronto, Ontario, Canada
  • Yuen, Darren A., St. Michael''s Hospital Keenan Research Centre for Biomedical Science, Toronto, Ontario, Canada
Background

Glomerulosclerosis is an important manifestation of diabetic glomerular injury. Studies of mesangial cells (the main producers of scar in the glomerulus) have mostly focused on biochemical stimuli (eg. high glucose, TGF-β). However, increasing evidence suggests that biomechanical stimuli such as extracellular matrix stiffening can also activate mesenchymal cells. In particular, the mechanosensory transcription co-factors YAP and TAZ appear to link matrix stiffness to fibrogenesis. Our goal was to study changes in glomerular stiffness as diabetic injury progresses.

Methods

We studied male Akita+/- Ren+/- mice at early (8 wk old, n = 8) and late (26 wk old, n = 6) time points. These mice develop diabetes and renin-mediated hypertension, resulting in progressive glomerulosclerosis that mimics human diabetic kidney disease. Male non-diabetic, normotensive Akita-/- Ren-/- mice served as healthy controls. Parameters of glomerular stiffness (atomic force microscopy, AFM) and histology (picrosirius red, type 1 collagen, and YAP/TAZ immunostaining) were measured and correlated. Glomerular stiffness was measured in a minimum of 30 glomeruli per kidney.

Results

Mean glomerular stiffness and glomerulosclerosis values increased with age in both the diabetic, hypertensive Akita+/- Ren+/- mice and their non-diabetic, normotensive Akita-/- Ren-/- controls, although at each time point, diabetic, hypertensive Akita+/- Ren+/- glomeruli were significantly stiffer and more scarred than glomeruli in healthy Akita-/- Ren-/- controls (Table 1). At both early and late stages of diabetic kidney injury, stiffness increased with glomerulosclerotic burden. Reflecting this increased stiffness, glomerular cell YAP/TAZ activity was increased in Akita+/- Ren+/- mice at 26 weeks compared to wild type controls, as evidenced by increased YAP/TAZ nuclear localization.

Conclusion

As glomerulosclerosis progresses in diabetes, the stiffness of glomeruli, as well as the activation of the mechanosensitive, pro-fibrotic transcription co-factors YAP and TAZ, increases. Taken together, our data suggest a novel biomechanical stimulus for glomerulosclerosis progression in diabetes.

 Plasma glucose
(mmol/L)
Body weight (g)Systolic blood pressure (mmHg)Urinary albumin (ug/day)Right
kidney/tibia
length (mg/mm)
Right
kidney/body
weight (mg/g)
Glomerula stiffness (kPa)
8 weeksAkita-/- Ren-/-10.85±1.423.2±1.876±7.4167.81149.96±3.78
7.78±2.2
1.6±0.5
Akita+/- Ren+/-27.75±5.024.4±2.1123±23.01989.9125
13.54±1.08
10.27±0.4
6.4±1.6
26 weeksAkita-/- Ren-/-9.03±1.543±2.958±6.2180.5073
12.7±1.05
6.08±1.0
5.8±0.9
Akita+/- Ren+/-30.1±2.335±2.6134±15.83440.7175
62.4±11.09
19.24±5.5
12.2±4.1