| Authors |
Gurley SB, Ghosh S, Johnson SA, Azushima K, Sakban RB, George SE, Maeda M, Meyer
TW, Coffman TM
|
| Submitted By |
Thomas Coffman on 10/5/2018 |
| Status |
Published |
| Journal |
Diabetes |
| Year |
2018 |
| Date Published |
|
| Volume : Pages |
67 : 2096 - 2106 |
| PubMed Reference |
30065034 |
| Abstract |
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease
worldwide, but its molecular pathogenesis is not well defined, and there are no
specific treatments. In humans, there is a strong genetic component determining
susceptibility to DN. However, specific genes controlling DN susceptibility in
humans have not been identified. In this study, we describe a mouse model
combining type 1 diabetes with activation of the renin-angiotensin system (RAS),
which develops robust kidney disease with features resembling human DN: heavy
albuminuria, hypertension, and glomerulosclerosis. Additionally, there is a
powerful effect of genetic background regulating susceptibility to nephropathy;
the 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is
resistant. To examine the molecular basis of this differential susceptibility,
we analyzed the glomerular transcriptome of young mice early in the course of
their disease. We find dramatic differences in regulation of immune and
inflammatory pathways, with upregulation of proinflammatory pathways in the
susceptible (129) strain and coordinate downregulation in the resistant
(C57BL/6) strain. Many of these pathways are also upregulated in rat models and
in humans with DN. Our studies suggest that genes controlling inflammatory
responses, triggered by hyperglycemia and RAS activation, may be critical early
determinants of susceptibility to DN.
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