Cellular and Molecular Mechanisms of AKI

Abstract

In this article, we review the current evidence for the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, using ischemic AKI as a model. Highlighted are the clinical relevance of cellular and molecular targets that have been investigated in experimental models of ischemic AKI and how such models might be improved to optimize translation into successful clinical trials. In particular, development of more context-specific animal models with greater relevance to human AKI is urgently needed. Comorbidities that could alter patient susceptibility to AKI, such as underlying diabetes, aging, obesity, cancer, and CKD, should also be considered in developing these models. Finally, harmonization between academia and industry for more clinically relevant preclinical testing of potential therapeutic targets and better translational clinical trial design is also needed to achieve the goal of developing effective interventions for AKI.

Keywords: acute renal failure; kidney; pathophysiology of renal disease and progression.

Figure 1.

Involvement of mitochondria in ischemic AKI: Healthy mitochondria generate the ATP necessary for cellular health and, in the renal tubule, the energy needed for the movement of solute and water against gradients. Ischemia-reperfusion injury leads to rapid fragmentation of mitochondrial networks through a dynamic process termed fission regulated by proteins such as dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1). The mitochondrial fusion machinery includes mitofusin 1 (Mfn1), Mfn2 and optic atrophy 1. Fragmented mitochondria appear to be a less efficient source of ATP and can undergo the MPT. MPT results in mitochondrial swelling from the influx of water, and it promotes cell death through the release of calcium (Ca⁺⁺), cytochrome c (Cyt c), and other proapoptotic proteins. Damaged mitochondria can be cleared and recycled through mitophagy, the first step of which is envelopment of the injured mitochondrion by a double-membrane structure termed the autophagosome (shown in green). Finally, in surviving cells, mitochondrial biogenesis results in an expansion of mitochondrial mass through regulated gene expression of structural and enzymatic components of mitochondria. Reprinted from www.adqi.net, with permission.

Figure 2.

Validating targets from simple to context-specific experimental models of AKI and subsequently in human AKI. Several therapeutic targets (red circles) may be identified by initial studies in simple experimental models of AKI. These should then be tested in more context-specific experimental models of AKI. Some therapeutic targets, albeit a smaller number, may be directly validated in context-specific animal models (yellow, blue, and light green circles). On the basis of studies in animal models (simple or context-specific), a limited number of therapeutic targets may be available for testing in human AKI. It is important to relate the findings seen with a given therapeutic target in human studies back to the experimental model system to gain better understanding of underlying mechanism(s). Reprinted from www.adqi.net, with permission.