Inflammation and Immunity Pathways Regulate Genetic Susceptibility to Diabetic Nephropathy

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.

Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

“…1 DM is associated with severe damage to multiple organ systems, such as the heart, eyes, and kidneys. [2][3][4] Recently, increasing attention has been paid to the pathological changes in the brain induced by DM. Diabetes-induced brain injury manifests as neurodegeneration, cerebral infarction, and progressive cognitive decline.…”

Effect modification of the association between plasma glucose and diabetic kidney disease by hypersensitive C-reactive protein in patients with diabetes mellitus

“…Previous studies have demonstrated that there might be a strong effect of genetic susceptibility to in uence development of DKD in both animal [25][26][27] and human beings [28,29]. Gurley and his colleagues found a marked triggering of immune and in ammatory gene expression pro les in the mice with DM was associated with susceptibility to development of DKD [8]. Given the fact that hs-CRP is one of the in ammatory biomarkers, the aforementioned ndings, at least partly, support our current results that hs-CRP modi ed the association of blood glucose and DKD.…”

“…In one animal experiment, there existed a marked triggering of immune and in ammatory gene expression pro les in the diabetic mice that developed DKD; by contrast, these pathways were coordinately down-regulated in the counterparts protected from kidney injury, suggesting in ammation and immune responsiveness may be critical features determining susceptibility of DKD [7,8]. Several clinical studies also showed activation in ammatory biomarkers, i.e.…”

Functional methylome analysis of human diabetic kidney disease

“…In our review of the literature, changes in TNF levels are not fully recapitulated in mouse DKD models. A recent paper by Gurley et al (8) proposed that an immune/ cytokine expression profile can also distinguish susceptible and resistant strains of mice, indicating that TNF activation might be an indicator of kidney disease susceptibility in mice as well. Although TNF is a key disease biomarker in patients with diabetes mellitus, the mechanism of TNF activation is unclear.…”