*5.3. Kidney Inflammation*

Kidney inflammation is a feature of both AKI and CKD. TWEAK is a proinflammatory cytokine of the TNF superfamily that promotes AKI and CKD [67,68]. A key feature of the TWEAK cytokine is that, contrary to TNF, it recruits the NIK-mediated, non-canonical pathway for activation of the NFκB transcription factor in kidney cells on top of the canonical pathway for NFκB activation [69–73]. NFκB is a key proinflammatory transcription factor that also downregulates kidney protective molecules [74]. Non-canonical NFκB is characterized by the nuclear translocation of RelB/NFκB2 p52 heterodimers [75]. Interestingly, the RelB subunit of NFκB directly binds *BMAL1* and acts as a negative regulator of circadian gene expression [76]. TWEAK also downregulates the kidney production of Klotho, an antiaging factor that is mainly expressed in the kidney, thus, potentially contributing to the accelerated aging of CKD [77,78]. Although the decrease in Klotho is mediated by the canonical NFκB pathway, it is nonetheless integrated within the cell response to TWEAK characterized by downregulation of tissue protective factors, as is a decrease in the mitochondrial biogenesis master regulator PGC1 α [79,80]. In his regard, RelB also couples with the bioenergy NAD (+) sensor sirtuin 1 (SIRT1) to modulate cell metabolism and mitochondrial bioenergetics [81].

Kidney fibrosis sis very tightly linked to inflammation. In this regard, Smad3, a key signaling effector for the profibrotic cytokine TGFβ1, has circadian expression and modulates the expression of circadian rhythm genes such as *Dec1*, *Dec2*, and *Per1* [82].
