Abstract Body: Background: Chronic kidney disease (CKD) is a devastating disease characterized by the progressive deterioration of renal functions. Sympathetic overactivation is a key feature of CKD that contributes to hypertension, heart failure, and cardiac arrhythmia all play a critical role in worsening CKD and its complications. The mechanisms underlying sympathetic overactivation in CKD are not clearly understood. Emerging evidence suggests that microglial cells mediated neuroinflammation in the sympathetic control brain areas such as the paraventricular nucleus (PVN) of the hypothalamus plays an important role in the pathology of several cardiovascular disorders involving sympathetic overactivation. Thus, the goal of the present study is to test the hypothesis that increased microglia-mediated neuroinflammation in sympathetic control areas could be involved in sympathetic overactivation in CKD.
Methods: 10–12-week-old C57/BL6 male mice (n=12) randomized to either 5/6 nephrectomy (Nx) or Sham surgery. After 4 weeks, blood pressure using a Millar catheter was recorded for spectral analysis of heart rate variability (HRV). Brain sections containing PVN were evaluated for immunostaining protein markers of activated microglia (Ionized calcium binding adaptor molecule 1). Further, blood samples were analyzed for plasma norepinephrine levels. Comparisons between groups were made using a t-test and a p-value <0.05 was accepted as significant.
Results: Mice with 5/6 Nx showed a significant increase in the ratio of low frequency (LF) to high frequency (HF) (LF:HF; Nx: 0.60+ 0.22; Sham: 0.24+0.14) (p<0.05) compared to the Sham mice. Plasma levels of norepinephrine (NE) were also elevated in 5/6 Nx mice (p<0.001). These data indicate sympathetic activation in CKD. Further, Nx mice had a significant increase in total number of microglia (resting + activated) in the PVN (Nx: 16.2+ 2.1; Sham: 13.8+2.4) (p<0.05) compared to Sham mice. Similarly, the number of activated microglia were also increased in the PVN of Nx mice (Nx: 10.25+ 2.2; Sham: 3.2+0.8) (p<0.05) indicating increased microglia-mediated neuroinflammation in CKD.
Conclusion: Our findings, for the first time, indicate that microglia-mediated neuroinflammation at least in part is involved in sympathetic activation and development of CKD. Further studies are underway to determine if inhibition of neuroinflammation in these brain areas restores sympathetic overactivation thereby preventing the progression of CKD.