Abstract: FR-PO194
Lats2 Ablation Exacerbates Severe Ischemia/Reperfusion-Induced Renal Maladaptive Repair Through the Upregulation of p53
Session Information
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Zhang, Chi, Shanghai General Hospital, Shanghai, China
- Zheng, Zhihuang, Shanghai General Hospital, Shanghai, China
- Wu, Huijuan, Fudan University School of Basic Medical Sciences, Shanghai, China
- Liu, Jun, Shanghai General Hospital, Shanghai, China
Background
Incomplete recovery of AKI can lead to long-term functional deficits and CKD. The Hippo pathway plays a regulatory role in the pathogenesis and repair of AKI and CKD progression. LATS2, a negative regulator of YAP in the Hippo pathway, has been proved to have a strong association with cell apoptosis independent of YAP. p53 has been known to mediate the progression of cell apoptosis and maladaptive kidney repair after AKI. Nevertheless, the relationship between LATS2 and p53 in post-AKI renal maladaptive repair remains far from clear.
Methods
We established proximal tubule Lats2 conditional knockout (Lats2-CKO) mouse models. Then we constructed a mouse model of maladaptive kidney repair after severe kidney injury (unilateral I/R-induced AKI) on both Lats2-CKO and WT mice, and assessed the fibrotic state, inflammatory cellular infiltration, apoptosis and p53 expression in post-AKI kidney tissue. Next, we used the pharmacological p53 inhibitor Pifithrin-α (PFT-α) to treat post-IRI mice for 14 days. Hypoxia and reoxygenation (H/R) was used to mimic I/R in vitro.
Results
At 14 days after I/R, Lats2-CKO mice represented more severe tubulointerstitial damage than WT mice. Masson trichrome, Sirius red staining, and α-SMA staining suggested that fibrosis is exacerbated in renal maladaptation in response to Lats2 knockout. F4/80 and CD3 renal positive staining indicated more severe I/R-induced macrophage and T cell infiltration in Lats2-CKO mice. Moreover, we found that proximal tubule-specific Lats2 knockout upregulates p53 expression, and also induces upregulation of p21 and Bax and downregulation of Bcl-2 and Bcl-xL, accompanied by higher rate of cellular apoptosis. In vivo administration of PFT-α in post-IRI mice reduced renal fibrosis, immune cell infiltration and apoptosis in both Lats2-CKO and WT group. Interestingly, in vitro experiments showed that Lats2 overexpression elevated p53 expression under vehicle condition, whereas suppressed p53 expression with H/R treatment, which indicated that H/R stress could revert the role of Lats2 on modulating p53 expression.
Conclusion
This study indicates that specific Lats2 knockout on renal proximal tubular epithelial cells exacerbates tubulointerstitial fibrosis, immune cell infiltration, apoptosis in ischemic AKI-induced tubular maladaptive repair through the upregulation of p53.
Funding
- Government Support – Non-U.S.