Kidney Week

Abstract: SU-OR09

Developmental Reprograming of Kidney Resident Macrophages During Human AKI and Its Implications to CKD

Session Information

• AKI Mechanisms: Research Abstracts
  October 25, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Zarjou, Abolfazl, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Abolfazl Zarjou, MD, PhD, FASN



Abolfazl Zarjou, M.D., Ph.D, FASN is an Assistant Professor at the Department of Medicine, Division of Nephrology. He is an active physician-scientist with research interests focused on the iron metabolism/ferritin system in the context of acute kidney injury and cardiovascular complications of CKD. His research is currently supported by a K08 award and SSCI-Research Scholar award to decipher the potential causal relationship between iron metabolism derangements during advanced CKD and vascular calcification.

• Mrug, Elias, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Elias Mrug,

• Zimmerman, Kurt, The University of Oklahoma, Norman, Oklahoma, United States

Kurt Zimmerman,

• Chen, Jiandong, Emory University, Atlanta, Georgia, United States

Jiandong Chen,

• Crossman, David K., The University of Alabama at Birmingham, Birmingham, Alabama, United States

David K. Crossman,

• Rosenblum, Frida, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Frida Rosenblum,

• Chumley, Phillip H., The University of Alabama at Birmingham, Birmingham, Alabama, United States

Phillip H. Chumley,

• Zhou, Juling, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Juling Zhou,

• Agarwal, Anupam, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Anupam Agarwal,

• George, James F., The University of Alabama at Birmingham, Birmingham, Alabama, United States

James F. George,

• Yoder, Bradley K., The University of Alabama at Birmingham, Birmingham, Alabama, United States

Bradley K. Yoder,

• Cui, Xiangqin, Emory University, Atlanta, Georgia, United States

Xiangqin Cui,

• Mrug, Michal, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Michal Mrug,

Background

Kidney tissue-resident macrophages (KRM) promote naturally progressing or AKI-induced cystic renal disease in mice. AKI also reprograms KRM into an early development state in mice. The relevance of KRM to human AKI and chronic kidney disease (CKD) remains mostly elusive.

Methods

We characterized KRM expression in renal biopsies and urine sediment from patients with AKI and non-AKI controls using a 255 gene Nanostring Inflammation panel. We mapped differentially expressed genes to single-cell RNA sequencing (scRNAseq) data from the Mouse Cell Atlas. We identified candidate injury-induced KRM markers and supported their validity in several available gene expression AKI- and CKD-relevant datasets (using limma package empirical Bayes smoothing in R).

Results

Both acute interstitial nephritis (AIN) and acute tubular necrosis (ATN) trigger transcriptional changes in similar genes (more prominently in AIN despite higher serum creatinine in ATN). Mapping of these AKI-regulated genes to normal adult kidney single scRNAseq data revealed the best fit for cell clusters defined by transcriptional signatures of KRMs. Such a fit was even stronger when the AKI-regulated genes were mapped to fetal kidney scRNAseq data. A similar fit was obtained by analyses of bulk RNAseq data of urine sediment from patients with AKI. Based on the strength of these associations, we prioritized C1qa, C1qb, C3ar1, Tlr1, Itgb2, Ccr7 and Ifit1 as transcriptional signatures of injury-induced KRMs. We validated the relevance of these candidate markers to the following: renal aging, protective effects of caloric restriction, and drug-induced forms of AKI in mice, pre-cystic kidney milieu in the model of polycystic kidney disease in a rat, and CKD including focal segmental glomerulosclerosis in human patients.

Conclusion

Together, we point to a KRM-like transcriptional response as a hallmark feature of AKI and CKD across species. The better fit of this response to fetal scRNAseq data supports the AKI-induced developmental reprogramming in human kidneys. A similar pattern of these responses in kidney tissues and urine cells points to urine-derived KRM assessment as an alternative to renal biopsies.

Funding

• NIDDK Support