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Abstract: SA-PO128

Grhl2-Deficient Mice Are Protected from Renal Fibrosis After Ischemic AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Boivin, Felix, Max Delbrück Center, Berlin, Germany
  • Müller, Dominik, Charité, Berlin, Germany
  • Schmidt-Ott, Kai M., Charite - Universitaetsmedizin Berlin, Berlin, Germany

Ischemic acute kidney injury disrupts epithelial tight junctions and induces a loss of epithelial cell polarity in the tubules of the nephron and collecting duct, leading to increased urine output and decreased urine osmolality. While the kidney can re-establish epithelial barrier integrity following injury, it is at an increased risk of developing fibrosis during recovery due to the activation of maladaptive repair mechanisms. Our group recently demonstrated that a transcription factor termed Grhl2 controls epithelial barrier formation of the collecting duct and is critical for renal osmoregulation. We showed that mice deficient for Grhl2 fail to properly concentrate urine and as a result exhibit reduced urine osmolality and develop diabetes insipidus. The relationship between the collecting duct barrier integrity and recovery post-injury is unclear.


To test this, we generated mice deficient for Grhl2 specifically in the collecting duct epithelium (Grhl2 CD - / -). We subjected these mice, along with their control littermates, to kidney injury via unilateral ischemia of the left kidney for 25 minutes. Subsequently, we investigated renal injury and regeneration by allowing the mice to recover for reperfusion periods of 1, 3, 7, or 21 days.


Semi-quantitative scoring of tubular damage in the initial phase of injury, at 1 and 3 days, did not reveal any significant differences between Grhl2CD-/- mice and controls. During the late recovery phase, 7 days post-ischemia, however, we observed a 38,52% decrease in tubular damage in Grhl2CD-/- mice (45.48% vs 27.96%, p<0.05). Additionally, we observed a 62.59% reduction in overall interstitial fibrosis 21 days post-ischemia in Grhl2CD-/- compared to control littermates (10.43% vs 6.53%, p<0.05). Further analysis of extracellular matrix components fibronectin and collagen IV, and the myofibroblast marker a-Smooth Muscle Actin, revealed marked reductions in Grhl2CD-/- mice. Additionally, we observed a significant reduction in mRNA expression of pro-inflammatory cytokines TNF-a (1.019 vs 0.4917, p<0.05) and IL-6 (1.027 vs 0.511, p<0.05) in Grhl2CD-/- mice 21 days post-ischemia.


Grhl2-deficient mice display an improved renal recovery following injury, raising the possibility that collecting duct epithelial barrier function and/or the intrarenal osmotic gradient contribute to renal recovery.


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