Stroke is a leading cause of mortality and morbidity, with long-term debilitating effects. Accumulating evidence from experimental studies as well as observational studies in patients suggests a cross talk between the brain and kidney after stroke. Stroke may lead to kidney dysfunction which can adversely impact patient outcome. In this review article, we discuss the epidemiology and mechanisms of brain–kidney interaction following ischemic stroke. Specifically, we discuss the role of the central autonomic network, autoregulation, inflammatory and immune responses, the role of extracellular vesicles and their cargo microRNA, in mediating brain–kidney interaction following stroke. Understanding the bidirectional nature of interaction between the brain and kidney after cerebral injury would have clinical implications for the treatment of stroke and overall patient outcome.
Cdc37 is a molecular chaperone that is important for the stability and activity of several protein kinases, including Cdk4 and Raf1. We first determined, using in vitro assays, that Cdc37 binds to the amino-terminal lobe of Cdk4. Subsequent mutagenesis revealed that Gly-15 (G15A) and Gly-18 (G18A) were critical for Cdc37-Cdk4 complex formation. Gly-15 and Gly-18 of Cdk4 are within the conserved Gly-X-Gly-X-X-Gly motif that is required for ATP binding to the kinase. Mutation of either glycine at the equivalent positions of Raf1 (G358A and G361A) also inhibited Cdc37 binding to Raf1. Replacing another conserved residue critical for ATP binding and kinase activity, Lys-35 (K35A), reduced Cdc37-Cdk4 complex formation but to a lesser extent. The interaction of Cdk4 with Cdc37 in vitro was not sensitive to changes in ATP levels. Cell-based assays indicated that Cdk4 G15A and Cdk4 G18A were present at the same level as wild type Cdk4. Equivalent amounts of p16 bound to Cdk4 G15A and Cdk4 G18A relative to wild type Cdk4, suggesting that Cdk4 G15A and Cdk4 G18A adopt significant tertiary structure. However, in contrast to wild type Cdk4, Cdk4 G15A , and Cdk4 G18A had greatly reduced binding of cyclin D1, Cdc37, and Hsp90. Importantly, overexpression of Cdc37 not only stimulated cyclin D1 binding to wild type Cdk4 but also restored its binding to Cdk4 G15A . Under the same conditions, p16 binding to wild type Cdk4 was suppressed. Our findings show that the interaction of Cdc37 with its client protein kinases requires amino acid residues within a motif that is present in many protein kinases.
BackgroundThe mechanisms underlying worse outcome at advanced age after cardiac arrest (CA) and resuscitation are not well understood. Because protein homeostasis (proteostasis) is essential for cellular and organismal health, but is impaired after CA, we investigated the effects of age on proteostasis‐related prosurvival pathways activated after CA.Methods and ResultsYoung (2–3 months old) and aged (21–22 months old) male C57Bl/6 mice were subjected to CA and cardiopulmonary resuscitation (CPR). Functional outcome and organ damage were evaluated by assessing neurologic deficits, histological features, and creatinine level. CA/CPR‐related changes in small ubiquitin‐like modifier conjugation, ubiquitination, and the unfolded protein response were analyzed by measuring mRNA and protein levels in the brain, kidney, and spinal cord. Thiamet‐G was used to increase O‐linked β‐N‐acetylglucosamine modification. After CA/CPR, aged mice had trended lower survival rates, more severe tissue damage in the brain and kidney, and poorer recovery of neurologic function compared with young mice. Furthermore, small ubiquitin‐like modifier conjugation, ubiquitination, unfolded protein response, and O‐linked β‐N‐acetylglucosamine modification were activated after CA/CPR in young mice, but their activation was impaired in aged mice. Finally, pharmacologically increasing O‐linked β‐N‐acetylglucosamine modification after CA improved outcome.ConclusionsResults suggest that impaired activation of prosurvival pathways contributes to worse outcome after CA/CPR in aged mice because restoration of proteostasis is critical to the survival of cells stressed by ischemia. Therefore, a pharmacologic intervention that targets aging‐related impairment of proteostasis‐related pathways after CA/CPR may represent a promising therapeutic strategy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.