Identifying Common Molecular Mechanisms in Experimental and Human Acute Kidney Injury

https://doi.org/10.1016/j.semnephrol.2022.10.012Get rights and content

Summary

Acute kidney injury (AKI) is a highly prevalent, heterogeneous syndrome, associated with increased short- and long-term mortality. A multitude of different factors cause AKI including ischemia, sepsis, nephrotoxic drugs, and urinary tract obstruction. Upon injury, the kidney initiates an intrinsic repair program that can result in adaptive repair with regeneration of damaged nephrons and functional recovery of epithelial activity, or maladaptive repair and persistence of damaged epithelial cells with a characteristic proinflammatory, profibrotic molecular signature. Maladaptive repair is linked to disease progression from AKI to chronic kidney disease. Despite extensive efforts, no therapeutic strategies provide consistent benefit to AKI patients. Since kidney biopsies are rarely performed in the acute injury phase in humans, most of our understanding of AKI pathophysiology is derived from preclinical AKI models. This raises the question of how well experimental models of AKI reflect the molecular and cellular mechanisms underlying human AKI? Here, we provide a brief overview of available AKI models, discuss their strengths and limitations, and consider important aspects of the AKI response in mice and humans, with a particular focus on the role of proximal tubule cells in adaptive and maladaptive repair.

Section snippets

Zebrafish

AKI was first modeled in goldfish in 1990 through the intraperitoneal injection of hexachlorobutadiene.13 Subsequently, AKI has been explored in several other fish species using gentamicin treatment to induce nephrotoxic damage, bacterial infection to model sepsis, and laser ablation to induce targeted cell death.14, 15, 16 Given practical and experimental considerations such as husbandry, size, fecundity, life span, and, importantly, genetics, the zebrafish is now the most widely used fish in

CELLULAR AND MOLECULAR MECHANISMS IN EXPERIMENTAL AND HUMAN AKI

Most of our knowledge of the pathophysiology underlying mammalian AKI is derived from rodent models, because kidney biopsies are rarely performed in the acute phase of AKI in humans. In the following, we discuss selected aspects of the AKI response, highlighting common mechanisms between mice and humans. We focus on IRI as a highly prevalent cause of AKI, and its effect on PTCs, since PTCs are the most abundant cell type in the kidney and play a central role in both adaptive and maladaptive

CONCLUSIONS

Animal models have greatly enhanced our understanding of the molecular mechanisms underlying AKI and many features of both adaptive and maladaptive renal repair are conserved between mice and humans. However, none of the available model systems fully recapitulates the astounding complexity of human AKI, and failures of translational AKI studies highlight the need for a better understanding of human AKI pathophysiology on the one hand, and of the strengths and limitations of experimental AKI

Acknowledgment

We apologize to all researchers whose work could not be discussed owing to space limitations. We thank Dr. Seth Ruffins and the Optical Imaging Facility of the University of Southern California Stem Cell Department for technical support.

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  • Financial support: Supported by the German Research Foundation postdoctoral scholarship GE 3179/ 1-1 (L.M.S.G.), and the work in Andrew P. McMahon's laboratory is supported by grants from the National Institutes of Health (UC2 DK126024-01, R01 DK054364, R01 DK121409, and R01 DK126925-01) to Andrew P. McMahon.

    Conflict of interest statement: Andrew P. McMahon serves as a scientific advisor to Novartis, TRESTLE Biotherapeutics, eGENESIS, and IVIVA Medical. The remaining author reports no conflict of interest.

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