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Abstract: PO0690

Differences in Kidney Integrin Alpha-2 Expression Between Humans and Preclinical Models

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Pissios, Pavlos, CVM, Janssen Research and Development LLC, Boston, Massachusetts, United States
  • Rankin, Matthew M., CVM, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Chen, Tao, NCS, Janssen Research and Development LLC, Shanghai, China
  • Bukanov, Nikolay O., CVM, Janssen Research and Development LLC, Boston, Massachusetts, United States
  • Breyer, Matthew Douglas, CVM, Janssen Research and Development LLC, Boston, Massachusetts, United States
  • Magnone, Maria chiara, CVM, Janssen Research and Development LLC, Boston, Massachusetts, United States
Background

Integrin α2 (ITGA2) forms heterodimers with integrin β1 and is one of the four collagen binding integrins with preference for collagen I. Published results implicate α2 in the regulation of kidney injury. Whole body deletion of integrin α2 protects mice from kidney injury in the 5/6 nephrectomy and adriamycin models of nephropathy, and α2 expression in mesangial cells has been proposed to contribute to kidney pathology through regulation of matrix production. We assessed the distribution of α2 protein in human DKD kidney and in multiple preclinical species to get a better understanding of the cell types expressing α2.

Methods

Human kidneys from normal and DKD subjects, as well as kidneys from diabetic mice, rats and cynomolgus monkeys were evaluated by immunohistochemistry (IHC) for α2 expression. Staining antibody was validated with kidneys from α2-KO mice. Identification of α2-positive kidney cell types and scoring was performed by a trained pathologist. Protein expression was compared with RNA expression in snRNAseq datasets from human DKD kidneys and kidneys from db/db mice.

Results

All species showed strong staining in the medulla, but significant differences were noted in the cortical α2 expression between humans and other species. Mainly mesangial, endothelial and distal tubular staining was seen in human kidney cortex. Podocytes were negative while proximal tubules stained weakly. Consistent with IHC data, strong a2 expression in human distal tubules and weaker expression in proximal tubules and glomerular cell types is seen in snRNAseq data. In contrast, mice showed mainly podocyte and endothelial staining. Mesangial cells and mouse proximal tubules were negative for α2, and distal tubules in the cortex stained weakly. Rat kidneys were negative for glomerular α2 expression with medium to strong positivity in the distal tubules of the cortex. Finally, cynomolgus monkeys showed α2 expression in all glomerular cell types: podocytes, endothelial and mesangial, weak staining in proximal and medium to strong staining in distal tubules. Decreased α2 glomerular staining was observed in DKD kidneys compared to normal kidneys.

Conclusion

Differences in integrin α2 cellular expression pattern must be considered when extrapolating function from lower to higher species.

Funding

  • Commercial Support