DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury

Abstract

Rationale: Acute kidney injury (AKI) is pathologically characterized by renal tubular epithelial cell (RTEC) death and interstitial inflammation, while their pathogenesis remains incompletely understood. Dual-specificity phosphatase 2 (DUSP2) recently emerges as a crucial regulator of cell death and inflammation in a wide range of diseases, but its roles in renal pathophysiology are largely unknown. Methods: The expression of DUSP2 in the kidney was characterized by histological analysis in renal tissues from patients and mice with AKI. The role and mechanism of DUSP2-mediated inhibition of tubular epithelial cell pyroptosis in AKI were evaluated both in vivo and in vitro , and confirmed in RTEC-specific deletion of DUSP2 mice. Results: Here, we show that DUSP2 is enriched in RTECs in the renal tissue of both human and mouse and mainly positions in the nucleus. Further, we reveal that loss-of-DUSP2 in RTECs not only is a common feature of human and murine AKI but also positively contributes to AKI pathogenesis. Especially, RTEC-specific deletion of DUSP2 sensitizes mice to AKI by promoting RTEC pyroptosis and the resultant interstitial inflammation. Mechanistic studies show that gasdermin D (GSDMD), which mediates RTEC pyroptosis, is identified as a transcriptional target of activated STAT1 during AKI, whereas DUSP2 as a nuclear phosphatase deactivates STAT1 to restrict GSDMD-mediated RTEC pyroptosis. Importantly, DUSP2 overexpression in RTECs via adeno-associated virus-mediated gene transfer significantly ameliorates AKI. Conclusion: Our findings demonstrate a hitherto unrecognized role of DUSP2-STAT1 axis in regulating RTEC pyroptosis in AKI, highlighting that DUSP2-STAT1 axis is an attractive therapeutic target for AKI.

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

“…The AKI-to-CKD mouse model refers to previous studies ( Xiong et al, 2022 ). Briefly, 8–12 weeks male mice were anesthetized, followed by an abdominal incision, and the renal pedicles of both kidneys were clamped for 32 min to induce IRI.…”

“…Scr and BUN were detected using a commercial kit (NJJCBIO, China) according to previously reportt following manufacturer’s instructions ( Xiong et al, 2022 ).…”

Systemic inflammation response index as a prognostic factor for patients with sepsis-associated acute kidney injury: a retrospective observational study

“…Similar to this, one pathological feature of AKI is inflammation in the renal interstitium. 17 This inflammatory response represents the primary host defense mechanism against infection and plays a crucial role in initiating and supporting the necessary repair processes for functional recovery following injury. 18 Classic inflammatory indicators, including the white blood cell count and its subtypes, notably the neutrophil and lymphocyte counts, have a well-established place in clinical practice.…”

Pyroptosis: The Determinator of Cell Death and Fate in Acute Kidney Injury

“…Other studies have shown that vitamin D3 can reduce the production of ROS and inhibit the nuclear factor kappa B (NF-κB) signaling pathway, thus hindering pyroptosis [31]. Salvianolic acid B, a water-soluble compound extracted from Salvia, has potent antioxidant properties, and Pang et al [32] discovered that it significantly decreases the expression of NLRP3, Caspase-1, GSDMD, and IL-1β in kidney tissues of the IRI-AKI group. In vitro experiments have further confirmed that salvianolic acid B pretreatment helps increase Nrf2 levels by inhibiting oxidative stress, pro-inflammatory cytokines, and NLRP3 inflammasome activation, reducing pyroptosis.…”