SERCA2 Deficiency Promotes AKI by Regulating Endoplasmic Reticulum-Mitochondria Cross-Talk via Voltage-Dependent Anion Channels

Background: Acute kidney injury (AKI) is a serious medical condition characterized by a rapid loss of renal function. SERCA2 is a critical enzyme located in the sarcoplasmic reticulum and endoplasmic reticulum (ER) to maintain calcium homeostasis. While the relationship between SERCA2 and AKI and its regulatory mechanism remains unclear. Methods: Renal proximal tubule-specific ATP2a2-knockdown mice (ATP2a2tKD) and control mice (ATP2a2fl/wt) were used to determine its function and potential mechanisms in AKI established by ischemia/reperfusion injury (IRI) and lipopolysaccharide (LPS). Results: SERCA2 was significantly decreased in proximal tubules of kidneys from AKI patients. Similar observations were also obtained from kidneys of IRI and LPS induced AKI models. Conditional knockdown of SERCA2 exacerbated AKI induced by IRI and LPS. SERCA2 deficiency aggravated ER stress, mitochondria dysfunction and calcium overloading. Mechanically, SERCA2 binds to voltage-Dependent Anion Channel (VDAC), thereby regulating calcium homeostasis and ER-mitochondria crosstalk. Conclusion: Our results revealed that SERCA2 play a protective role in AKI by regulating ER-mitochondria crosstalk and calcium homeostasis, thereby identifying a novel and important therapeutic target for AKI.SERCA2 deficiency in tubular epithelial cells exacerbates IRI and LPS-induced AKISERCA2 deficiency exacerbated ER stress and mitochondrial damage via VDAC