Background: Acute kidney injury (AKI) is a common medical condition that significantly increases the risk of developing chronic kidney disease (CKD), involving epithelial-mesenchymal transition (EMT), fibrosis and impaired kidney function. Necroinflammation and necroptosis play key roles in AKI. My project evaluates their impact in AKI to CKD/renal fibrosis progression across AKI models, identifying potential therapeutics to mitigate AKI and CKD/renal fibrosis risk.
Methods: Nephrotoxic agents (cisplatin [CDDP], pemetrexed [PEM], gentamicin [GM], and aristolochic acid-I [AA-I]) were used on HK2 cells for nephrotoxicity-AKI simulation. Ischaemia-reperfusion injury (IRI) induced-AKI was created in mice through renal clamping and in HK2 cells using oxygen-glucose deprivation (OGD). Sepsis associated-AKI (S-AKI) was induced by lipopolysaccharide (LPS). To demonstrate the participation of necroptosis, toll-like receptor (TLR), receptor for advanced glycation end products (RAGE), and c-Jun N-terminal Kinase (JNK), respective inhibitors or antagonists were applied to in vitro and in vivo experiments. The anti-EMT properties of Dexmedetomidine (Dex), an α2-adrenoceptor (α2-AR) agonist with renal-protective properties, were also investigated.
Results: CDDP, PEM, and AA-I significantly inducing necroptosis and EMT through TLR-4. The necroptosis inhibitor Necrostatin-1 (Nec-1) was able to alleviate these effects. GM, in contrast, induced apoptosis without significant EMT induction.
IRI triggered necroptosis and EMT both in vitro and in vivo, with Nec-1 showing protection. High mobility group box-1 protein (HMGB-1) was found to trigger EMT via TLR/JNK signalling.
In the S-AKI model, Dex attenuated LPS-induced renal injury and EMT via α2-adrenoceptor activation, inhibited necroinflammation, and showed protective effects against transforming growth factor-β1 (TGF-β1)-induced EMT, associated with JNK inhibition.
Conclusion: Necroptosis-associated necroinflammation is involved in AKI and subsequent EMT through TLR4/JNK cellular signalling pathways. These can be therapeutic targets for further development and potentially translate into clinical practice. Dex prevented necroinflammation and EMT, indicating its great value for clinical use but subjected further clinical studies.