Kidney Week

Abstract: TH-PO679

Transcriptomic Profile in Early versus Late Stages of Murine Diabetic Nephropathy

Session Information

• Diabetes Mellitus and Obesity: Basic - Experimental - I
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Diabetes

• 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

• Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Haichun Yang,

• Ericsson, Anette E., AstraZeneca R&D Molndal, Molndal, Sweden

Anette E. Ericsson,

• Reznichenko, Anna, AstraZeneca R&D Molndal, Molndal, Sweden

Anna Reznichenko,

• Sanchez, José, AstraZeneca, Molndal, Sweden

José Sanchez,

• William-Olsson, Lena, AstraZeneca R&D Molndal, Molndal, Sweden

Lena William-Olsson,

• Soderberg, Magnus, AstraZeneca, Molndal, Sweden

Magnus Soderberg,

• Granqvist, Anna, AstraZeneca R&D Molndal, Molndal, Sweden

Anna Granqvist,

• Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Raymond C. Harris,

• Vickers, Kasey C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Kasey C. Vickers,

• Fogo, Agnes B., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Agnes B. Fogo,

Background

Diabetic nephropathy (DN) has both glomerular and tubular injury. As a DN model, db/db/eNOS^-/- mice develop albuminuria and glomerular hypertrophy by age 10 weeks, and progress to nodular glomerular injury and reduced GFR by week 18. By RNA sequencing of isolated glomeruli and kidney cortex at different time points, we aimed to determine the transcriptional profiles critical for glomeruli vs tubular injury in DN.

Methods

db/db/eNOS^-/- (DN) and nondiabetic control db/eNOS^-/- mice (C) were sacrificed at week 10 and 18. The left kidney was harvested for isolating glomerular RNA, while the right kidney was used for extracting cortex RNA.

Results

86 genes from the glomerular extract showed different expression levels in DN vs C at week 10 (49 upregulated and 37 downregulated), and 5248 genes differed at week 18 (3599 up and 1649 down). 528 transcripts from cortical extracts were different in DN and C at week 10 (213 up and 315 down), and 684 transcripts differed) at week 18 (456 up and 228 down, but with overlap of only 116 genes in early vs late cortical samples. Metabolic processes, such as calcium, urea and P450 pathways, differed mostly in tubular vs glomerular analysis. Genes expressed at week 10 but not week 18 suggest a role in early but not progressive DN. We detected 118 upregulated and 188 downregulated genes at week 10, which did not differ at week 18 in DN. Among them, only 10 genes (7 up and 3 down) were present only in glomerular but not cortical samples, and include genes that modulate matrix, cell proliferation and tissue-specific differentiation.

Conclusion

In summary, by comparing db/db/eNOS^-/- vs db/eNOS^-/- mice, early vs late stage diabetics, and glomeruli vs cortex, we determined that there were marked increases in differentially modulated glomerular genes at later stages of disease, with different gene expression patterns in the tubulointerstitial compartment over time. These data indicate that glomerular and tubular mechanisms of DN injury are not identical, and also evolve over time.

Funding

• Commercial Support – AstraZeneca PLC