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Published on: March 4, 2022
Role of Fas (CD95) in tubulointerstitial disease induced by unilateral ureteric obstruction
1Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. jeremyh@u.washington.edu
Abstract:
Murine renal tubular epithelial cells and interstitial fibroblasts may express both Fas (CD95) death receptor and Fas ligand and are vulnerable to Fas-mediated death in vitro. We therefore hypothesized that an absence of renal Fas may protect resident cells from undergoing apoptosis. We performed unilateral ureteric ligation [producing unilateral ureteral obstruction (UUO)] in 6-wk-old normal control mice and C57Bl6/lpr mice, which express a nonfunctional Fas receptor. Obstructed kidneys were removed at days 3, 7, and 14 (n = 6 per group). Tubular cell apoptosis at day 7 was significantly reduced in lpr mice [21.8 +/- 5.8 vs. 45.7 +/- 7.6 cells/10 high-power fields (hpf), P < 0.02]. Importantly, there was no difference in tubular cell proliferation between normal and lpr mice at any time point studied. Interestingly, double labeling with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and the proximal tubule-specific antibody Fx1A indicated that the absence of Fas reduced distal but not proximal tubular death at day 7. In addition, there was no difference in interstitial cell apoptosis or proliferation, suggesting that Fas does not play a significant role in interstitial cell death. Importantly, inflammatory macrophage infiltration and ultimate collagen I deposition was unchanged in lpr mice. In conclusion, the absence of functional cell surface Fas in UUO provides distal tubular cells with partial protection from apoptosis but does not affect interstitial cell fate in this model of tubulointerstitial injury.
Insights
The absence of functional Fas receptors partially protected distal tubular cells from apoptosis during kidney injury in mice. However, this did not impact interstitial cell fate or overall kidney damage.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Renal tubular epithelial cells and interstitial fibroblasts can express Fas (CD95) death receptor and Fas ligand.
- These cells are susceptible to Fas-mediated apoptosis in vitro.
- The role of Fas in apoptosis during kidney injury requires further investigation.
Purpose of the Study:
- To investigate whether the absence of renal Fas protects resident cells from apoptosis in a mouse model of kidney injury.
- To determine the specific cell types and tubular segments affected by Fas-mediated apoptosis.
Main Methods:
- Unilateral ureteric obstruction (UUO) was performed on normal control mice and C57Bl6/lpr mice lacking functional Fas receptors.
- Kidneys were analyzed at 3, 7, and 14 days post-UUO for tubular cell apoptosis and proliferation using TUNEL and specific antibodies.
- Interstitial cell apoptosis and proliferation, as well as inflammatory macrophage infiltration and collagen deposition, were also assessed.
Main Results:
- Tubular cell apoptosis was significantly reduced in Fas-deficient (lpr) mice at day 7 post-UUO compared to controls.
- The absence of Fas specifically reduced apoptosis in distal tubular cells, but not proximal tubular cells.
- No significant differences were observed in tubular cell proliferation, interstitial cell apoptosis or proliferation, or inflammatory markers between the groups.
Conclusions:
- Absence of functional Fas receptors provides partial protection against apoptosis in distal tubular cells during UUO.
- Fas does not appear to play a significant role in interstitial cell apoptosis or proliferation in this model.
- These findings suggest a targeted role for Fas in distal tubule injury during obstructive nephropathy.
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