Progressive renal vascular proliferation and injury in obese Zucker rats

Abstract

Objective: Obesity, an independent risk factor for chronic kidney disease, may induce renal injury by promoting inflammation. Inflammatory cytokines can induce neovascularization in different organs, including the kidneys. However, whether obesity triggers renal neovascularization and, if so, its effect on renal function has never been investigated.

Methods: Blood pressure, proteinuria, and glomerular filtration rate (GFR) were measured in vivo. Renal microvascular (MV) architecture was studied by 3D micro-CT in lean and obese Zucker rats (LZR and OZR, n = 7/group) at 12, 22, and 32 weeks of age. Renal inflammation was assessed by quantifying interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and ED-1 expression, as renal fibrosis in trichrome-stained cross-sections.

Results: Mild inflammation and lower GFR was only observed in younger OZR, without renal fibrosis or changes in MV density. Interestingly, renal MV density increased in OZR at 32 weeks of age, accompanied by pronounced increase in renal IL-6 and TNF-alpha, ED-1+ cells, proteinuria, decreased GFR, and fibrosis.

Conclusions: This study shows increased renal cortical vascularization in experimental obesity, suggesting neovascularization as an evolving process as obesity progresses. Increased renal vascularization, possibly triggered by inflammation, may reflect an initially compensatory mechanism in obesity. However, increased inflammation and inflammatory-induced neovascularization may further promote renal injury as obesity advances.

Figure 1

Representative 3D tomographic images of the renal microcirculation and quantification of MV density per vessel diameter (0–80 μm, 80–120 μm, and 120–200 μm) from lean and obese Zucker rat kidneys after 12 (top row), 22 (middle row), and 32 (bottom row) weeks of age. Renal microvascular density significantly increased in obese Zucker rats after 32 weeks and longer exposure to obesity, compared to the lean animals. *p<0.05 vs. LZR.

Figure 2

Representative renal trichrome and ED-1 staining (top and bottom, respectively, x40) and quantification of renal fibrosis and inflammation in lean and obese Zucker rat kidneys after 12 weeks of age. Only a mild increase in inflammation was observed in OZR kidneys.

Figure 3

Representative renal trichrome and ED-1 staining (top and bottom, respectively, x40) and quantification of renal fibrosis and inflammation in lean and obese Zucker rat kidneys after 32 weeks of age. Inflammation, renal tubulo-interstitial fibrosis and glomerulosclerosis significantly increased after 32 weeks in obese Zucker rats.*p<0.05 vs. LZR.

Figure 4

Proteinuria and GFR (normalized per body weight) at 12 (top row) and 32 (bottom row) weeks of age in lean and obese Zucker rats. Despite a mild increase in proteinuria, and decreased in GFR (when normalized by body weight) was observed at 12 weeks of age. However, these changes were significantly accentuated after 32 weeks, as obesity progressed. *p<0.05 vs. LZR.