RESUMO
BackgroundAcute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood. MethodsWe performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1-2 hours after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI. ResultsHigh-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar. ConclusionThe study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies.
RESUMO
K(+) channels form a large family of membrane proteins that are expressed in a polarized fashion in any epithelial cell. Based on the transmembrane gradient for K(+) that is maintained by the Na(+)-K(+)-ATPase, these channels serve two principal functions for transepithelial transport: generation of membrane voltage and recycling of K(+). In this brief review, we will outline the importance of this ancient principle by examples of epithelial transport in the renal proximal tubule and gastric parietal cells. In both tissues, K(+) channel activity is rate-limiting for transport processes across the epithelial cells and essential for cell volume regulation. Recent experimental data using pharmacological tools and genetically modified animals have confirmed the original physiological concepts and specified the knowledge down to the molecular level. The development of highly active and tissue selective small molecule therapeutics has been impeded by two typical features of K(+) channels: their molecular architecture challenges the design of molecules with high affinity binding and they are expressed in a variety of tissues at the same time. Nevertheless, new insights into pathophysiology, e.g. that K(+) channel inhibition can block gastric acid secretion, render the clinical use of K(+) channel drugs in gastric disease and as kidney transport inhibitors highly attractive.
