Identifying Common Molecular Mechanisms in Experimental and Human Acute Kidney Injury
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.
REFERENCES (98)
- et al.
International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology
Lancet
(2015) - et al.
Acute kidney injury
Lancet.
(2019) - et al.
Rationale and design of the Kidney Precision Medicine Project
Kidney Int.
(2021) - et al.
New tides: using zebrafish to study renal regeneration
Transl Res.
(2014) - et al.
Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury
J Biol Chem.
(1998) - et al.
16 - urinary system
- et al.
Chapter 3 - the human kidney: parallels in structure, spatial development, and timing of nephrogenesis
- et al.
Human pluripotent stem cell-derived kidney organoids with improved collecting duct maturation and injury modeling
Cell Rep.
(2020) - et al.
Kidney repair and regeneration: perspectives of the NIDDK (Re)Building a Kidney consortium
Kidney Int.
(2022) - et al.
Human iPSC-derived renal organoids engineered to report oxidative stress can predict drug-induced toxicity
iScience.
(2022)
Phase II trials in drug development and adaptive trial design
JACC Basic Transl Sci.
Isolation of renal progenitor cells from adult human kidney
Am J Pathol.
Isolation and characterization of progenitor-like cells from human renal proximal tubules
Am J Pathol.
In vivo clonal analysis reveals lineage-restricted progenitor characteristics in mammalian kidney development, maintenance and regeneration
Cell Rep.
Intrinsic epithelial cells repair the kidney after injury
Cell Stem Cell.
Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis
Kidney Int.
Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis
Kidney Int.
Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease
EBioMedicine.
Multi-omic approaches to acute kidney injury and repair
Curr Opin Biomed Eng.
Kidney Disease: Improving Global Outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury
Kidney Int Suppl.
Urine neutrophil gelatinase-associated lipocalin identifies unilateral and bilateral urinary tract obstruction
Nephrol Dial Transplant.
Acute kidney injury
Nat Rev Dis Primers.
Molecular nephrology: types of acute tubular injury
Nat Rev Nephrol.
Recommendations on acute kidney injury biomarkers from the Acute Disease Quality Initiative Consensus Conference: a consensus statement
JAMA Netw Open.
Subclinical AKI: ready for primetime in clinical practice?
J Nephrol.
Unique transcriptional programs identify subtypes of AKI
J Am Soc Nephrol.
Bridging translation for acute kidney injury with better preclinical modeling of human disease
Am J Physiol Renal Physiol.
Bridging translation by improving preclinical study design in AKI
J Am Soc Nephrol.
Development of newly formed nephrons in the goldfish kidney following hexachlorobutadiene-induced nephrotoxicity
Toxicol Pathol.
Experimental models of acute kidney injury for translational research
Nat Rev Nephrol.
A fish model of renal regeneration and development
ILAR J.
Kidney development and disease in the zebrafish
J Am Soc Nephrol.
Histone deacetylase inhibitor enhances recovery after AKI
J Am Soc Nephrol.
Mammalian target of rapamycin mediates kidney injury molecule 1-dependent tubule injury in a surrogate model
J Am Soc Nephrol.
Identification of adult nephron progenitors capable of kidney regeneration in zebrafish
Nature.
Inhibition of histone deacetylase expands the renal progenitor cell population
J Am Soc Nephrol.
Animal models of renal dysfunction: acute kidney injury
Expert Opin Drug Discov.
A genetic model for in vivo proximity labelling of the mammalian secretome
Open Biol.
Cell-specific translational profiling in acute kidney injury
J Clin Invest.
TNF-α mediates increased susceptibility to ischemic AKI in diabetes
Am J Physiol Renal Physiol.
Severe renal mass reduction impairs recovery and promotes fibrosis after AKI
J Am Soc Nephrol.
Large animal models for translational research in acute kidney injury
Ren Fail.
Of mice and not men: differences between mouse and human immunology
J Immunol.
Modeling oxidative injury response in human kidney organoids
Stem Cell Res Ther.
Evaluation of cisplatin-induced injury in human kidney organoids
Am J Physiol Renal Physiol.
Nephron organoids derived from human pluripotent stem cells model kidney development and injury
Nat Biotechnol.
Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis
Nature.
Bioprinted pluripotent stem cell-derived kidney organoids provide opportunities for high content screening
bioRxiv.
High-throughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping
Cell Stem Cell.
Cited by (2)
Proximal tubule responses to injury: Interrogation by single-cell transcriptomics
2023, Current Opinion in Nephrology and HypertensionHow to Best Protect Kidneys for Transplantation—Mechanistic Target
2023, Journal of Clinical Medicine
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.