Electroacupuncture-Induced SUMOylation and ACE2 Replacement: Dual Approaches to Mitigate AKI Inflammation

Background: Septic acute kidney injury (AKI) and delayed graft function (DGF) after kidney transplantation are both driven by innate immune overactivation and inflammation. Electroacupuncture (EA) activates neuroimmune reflexes, but the downstream molecular mediators remain poorly defined. We hypothesized that EA induces SUMOylation to suppress systemic inflammation in septic AKI. Separately, we investigated ACE2 shedding in ischemic transplant-associated AKI and tested whether ACE2 supplementation via machine perfusion could mitigate DGF. Methods: A murine sepsis model (cecal ligation and puncture, CLP) was used with or without EA at ST36. Some animals received a SUMOylation inhibitor (TAK-981) or underwent splenectomy. Outcomes included serum TNF-α (ELISA), kidney injury (BUN/creatinine), and splenic SUMO1 expression (Western blot). In a separate ischemia-reperfusion model (30 min clamp with contralateral nephrectomy), we measured renal ACE2 protein/activity and urinary ACE2. In transplant studies, donor kidneys were machine-perfused with recombinant ACE2 (ACE2-618-ABD) before transplantation. Results: EA reduced serum TNF-α levels by 52.4% vs. untreated CLP (136 ± 18 pg/mL vs. 285 ± 24 pg/mL, p < 0.01) and lowered BUN (41.7 ± 3.9 vs. 62.2 ± 4.1 mg/dL, p < 0.01). EA increased SUMO1-conjugated protein in spleen lysates (p < 0.05 vs. sham). The anti-inflammatory effect of EA was abolished by TAK-981 (TNF-α: 264 ± 20 pg/mL) or splenectomy (p > 0.05 vs. untreated CLP). In the ischemia model, cortical ACE2 activity fell by 36.2% (p < 0.01), and urinary ACE2 increased ~11-fold (p < 0.001). In DGF kidneys, ACE2 protein was reduced by ~51% vs. control grafts (49 ± 9% vs. 100 ± 14%, p = 0.01). Kidneys perfused with recombinant ACE2 showed increased ACE2 activity (193 ± 21 RFU/μg vs. 115 ± 17 RFU/μg, p < 0.01) and reduced post-transplant creatinine (0.84 ± 0.08 vs. 1.21 ± 0.10 mg/dL, p = 0.02). Conclusion: EA induces a spleen-dependent SUMOylation pathway that suppresses TNF-driven inflammation in septic AKI. ACE2 shedding in ischemic AKI contributes to DGF pathogenesis, and ACE2 supplementation via machine perfusion improves renal recovery. These findings highlight two distinct, targetable pathways—SUMOylation and ACE2 signaling—for modulating innate immunity and improving kidney transplant outcomes.