Selective Wnt/β-Catenin Pathway Activation Concomitant With Sustained Overexpression of miR-21 is Responsible for Aristolochic Acid-Induced AKI-to-CKD Transition

Abstract

Acute kidney injury (AKI) is increasingly recognized as a cumulative risk factor for chronic kidney disease (CKD) progression. However, the underlying mechanisms remain unclear. Using an aristolochic acid (AA)-induced mouse model of AKI-to-CKD transition, we found that the development of tubulointerstitial fibrosis following AKI was accompanied with a strong activation of miR-21 and canonical Wnt signaling, whereas inhibition of miR-21 or selective silencing of Wnt ligands partially attenuated AKI-to-CKD transition. To explore the interaction between miR-21 and Wnt/β-catenin signaling, we examined the effects of genetic absence or pharmacologic inhibition of miR-21 on Wnt/β-catenin pathway expression. In miR-21−/− mice and in wild-type mice treated with anti-miR21 oligos, Wnt1 and Wnt4 canonical signaling in the renal tissue was significantly reduced, with partial reversal of renal interstitial fibrosis. Although the renal abundance of miR-21 remained unchanged after inhibition or activation of Wnt/β-catenin signaling, early intervention with ICG-001, a β-catenin inhibitor, significantly attenuated renal interstitial fibrosis. Moreover, early (within 24 h), but not late β-catenin inhibition after AA administration attenuated AA-induced apoptosis and inflammation. In conclusion, inhibition of miR-21 or β-catenin signaling may be an effective approach to prevent AKI-to-CKD progression.

IKKα aggravates renal fibrogenesis by positively regulating the Wnt/β‐catenin pathway

“…However, no data to date are available about the mechanism of IKKα on inducing kidney fibrosis. As is known that Wnt/β‐catenin pathway is involved in kidney fibrosis [37–45], our studies found active‐β‐catenin and snail were markedly increased in UIRI and UUO models which were down‐regulated when IKKα was knocked out, indicating that knockout of IKKα gene inhibits activation of wnt/β‐catenin pathway. In addition, the binding of IKKα and β‐catenin was studied in vitro.…”

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

“…A moderate increase in Wnt/β-catenin signaling is beneficial, but excessive activation of this pathway could trigger renal fibrosis (Guo et al, 2019;Sun et al, 2020). In addition, early intervention, but not late with β-catenin inhibitor significantly attenuates the apoptosis and inflammation induced by aristolochic acid (AA) (Kuang et al, 2021). Therefore, the dual role of Wnt/β-catenin signaling in CKD needs further study.…”

Driving role of macrophages in transition from acute kidney injury to chronic kidney disease

“…[ 2 ] The development of AKI-to-CKD is heterogeneous as this transition occurs in different patients and can be caused by multiple conditions, such as nephrotoxin, sepsis, ischemia-reperfusion, surgical operation, and cardiovascular diseases. [ 3 ]…”

“…[2] The development of AKI-to-CKD is heterogeneous as this transition occurs in different patients and can be caused by multiple conditions, such as nephrotoxin, sepsis, ischemia-reperfusion, surgical operation, and cardiovascular diseases. [3] Currently, the mechanism of this multifactorial process remains unclear. However, such information is crucial for developing treatment strategies to prevent the harmful progression of kidney injury.…”

“…Based on the findings of previous studies, the pooled adjusted hazard ratio of AKI-to-CKD is 4.3 compared with CKD without a history of AKI [2] . The development of AKI-to-CKD is heterogeneous as this transition occurs in different patients and can be caused by multiple conditions, such as nephrotoxin, sepsis, ischemia-reperfusion, surgical operation, and cardiovascular diseases [3] …”