Emerging links between endoplasmic reticulum stress responses and acute kidney injury

Abstract

All cell types must maintain homeostasis under periods of stress. To prevent the catastrophic effects of stress, all cell types also respond to stress by inducing protective pathways. Within the cell, the endoplasmic reticulum (ER) is exquisitely stress-sensitive, primarily because this organelle folds, posttranslationally processes, and sorts one-third of the proteome. In the 1990s, a specialized ER stress response pathway was discovered, the unfolded protein response (UPR), which specifically protects the ER from damaged proteins and toxic chemicals. Not surprisingly, UPR-dependent responses are essential to maintain the function and viability of cells continuously exposed to stress, such as those in the kidney, which have high metabolic demands, produce myriad protein assemblies, continuously filter toxins, and synthesize ammonia. In this mini-review, we highlight recent articles that link ER stress and the UPR with acute kidney injury (AKI), a disease that arises in ∼10% of all hospitalized individuals and nearly half of all people admitted to intensive care units. We conclude with a discussion of prospects for treating AKI with emerging drugs that improve ER function.

Keywords: chemical chaperone; molecular chaperone; proteostasis; renal physiology; unfolded protein response (UPR).

Graphical abstract

Figure 1.

Unfolded protein response (UPR) signaling pathways. The three integral membrane transducers of the UPR in mammalian cells and their most prominent downstream effects are indicated. Although specific details of how each transducer results in unique outcomes may differ, IRE1, ATF6, and PERK are all activated by the dissociation of a repressing molecular chaperone complex from their lumenal domains. As shown, dissociation is triggered by an increase in the concentration of misfolded proteins in the ER. In addition (not shown), UPR strength may also be modulated directly by misfolded proteins, and the pathway can also be initiated by lipid disequilibrium. ATF6 activation requires transport to the Golgi and subsequent cleavage (not shown). The cleaved ATF6 fragment then migrates to the nucleus and directly activates the transcription of target genes. In contrast, IRE1 splices an intron that represses translation of the XBP1 transcription factor, whereas PERK phosphorylates eIF2α, which slows translation and activates another transcription factor—ATF4—that initiates a CHOP-dependent proapoptotic pathway. See text for additional details, and note that only select examples of downstream UPR outcomes are shown.