Recent Publications

Inflammation and immunity pathways regulate genetic susceptibility to diabetic nephropathy.

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, 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.

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Fasting blood glucose, urinary AE, and renal pathology in mice. A: Compared with normal levels in WT mice, fasting blood glucose was significantly elevated in all of the Akita mouse groups during the period from 2 to 6 months of age, and there were no significant differences in blood glucose values between the various Akita mouse lines at these time points. B: Twenty-four–hour urinary AE was significantly higher in 24-week-old 129/SvEv strain (white bars) RenTg or Akita-RenTg mice compared with corresponding lines at 24 weeks on the C57BL/6 strain (black bars). Data are expressed as mean ± SEM. *P < 0.05; **P < 0.001 compared with C57BL/6; ‡P < 0.001 compared to 129/SvEv WT. C–F: Photomicrographs of periodic acid-Schiff–stained sections of mouse kidneys. Representative low- (C and E) and high-magnification (D and F) images of periodic acid-Schiff–stained kidney sections from 24-week-old 129/SvEv mice with RenTg alone (C and D) or 24-week-old double-heterozygous 129/SvEv Akita-RenTg mice (E and F). 129/SvEv RenTg mice have minimal pathological abnormalities, whereas 129/SvEv Akita-RenTg mice exhibit marked mesangial expansion and frank glomerular sclerosis with focal areas of interstitial inflammation.