| First Author | Srivastava A | Year | 2022 |
| Journal | Matrix Biol | PubMed ID | 35964866 |
| Mgi Jnum | J:328268 | Mgi Id | MGI:7334595 |
| Doi | 10.1016/j.matbio.2022.08.005 | Citation | Srivastava A, et al. (2022) RIPK3-MLKL signaling activates mitochondrial CaMKII and drives intrarenal extracellular matrix production during CKD. Matrix Biol |
| abstractText | Intrarenal extracellular matrix production is a prevalent feature of all forms of chronic kidney disease (CKD). The transforming growth factor-beta (TGFbeta) is believed to be a major driver of extracellular matrix production. Nevertheless, anti-TGFbeta therapies have consistently failed to reduce extracellular matrix production in CKD patients indicating the need for novel therapeutic strategies. We have previously shown that necroinflammation contributes to acute kidney injury. Here, we show that chronic/persistent necroinflammation drives intrarenal extracellular matrix production during CKD. We found that renal expression of receptor-interacting protein kinase-1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) increases with the expansion of intrarenal extracellular matrix production and declined kidney function in both humans and mice. Furthermore, we found that TGFbeta exposure induces the translocation of RIPK3 and MLKL to mitochondria resulting in mitochondrial dysfunction and ROS production. Mitochondrial ROS activates the serine-threonine kinase calcium/calmodulin-dependent protein kinases-II (CaMKII) that increases phosphorylation of Smad2/3 and subsequent production of alpha-smooth muscle actin (alphaSMA), collagen (Col) 1alpha1, etc. in response to TGFbeta during the intrarenal extracellular matrix production. Consistent with this, deficiency or knockdown of RIPK3 or MLKL as well as pharmacological inhibition of RIPK1, RIPK3, and CaMKII prevents the intrarenal extracellular matrix production in oxalate-induced CKD and unilateral ureteral obstruction (UUO). Together, RIPK1, RIPK3, MLKL, CaMKII, and Smad2/3 are molecular targets to inhibit intrarenal extracellular matrix production and preserve kidney function during CKD. |
