Renal‐Specific Dendritic Cell Depletion Reduces Urinary Interleukin 6 Levels Following Angiotensin II‐Mediated Hypertension and Dietary High Salt

Abstract

During hypertension, dendritic cells (DCs) have been shown to activate other immune cells and secrete cytokines, such as interleukin 6 (IL‐6). Recently, DCs were found to form an intricate network within the renal cortex and especially along the distal nephron. Studies reveal that renal‐specific DCs (rDCs) play an important role in the progression of hypertension. Previously, our data suggest that IL‐6 can increase sodium chloride cotransporter (NCC) expression and activity. We hypothesize that rDCs modulate intra‐renal levels of IL‐6 during hypertension or high salt (HS), which may affect distal nephron sodium reabsorption.To test this hypothesis, mice lacking a functional CX3CR1 chemokine receptor (CX3CR1‐EGFP+/+ or rDC mice) were used. CX3CR1 is required for DC localization to the kidney; thus these mice have a renal‐specific DC‐depletion. Mice were either given: vehicle or angiotensin II (AngII) (60ng/min, 28 days + 4% high salt) via osmotic minipump or fed a high salt (4%, 7 days) or normal diet. Systolic BP measurements were obtained with tail‐cuff plethysmography. Metabolic cage studies were performed and urine collected. Urine and serum were used to perform a cytokine array via Meso‐Scale Discovery system. Whole kidney cortex lysates were used for mRNA isolation and RT‐PCR.Mice with renal‐specific loss of DCs had a decreased systolic blood pressure at baseline. Following AngII hypertension, similar BP increases were observed (Δ38mmHg rDC vs. Δ36mmHg Wt). Baseline serum IL‐6 levels were not different; however, AngII‐infusion resulted in ≈3 fold decrease in IL‐6 mRNA in rDC mice when compared to Wt mice. At baseline, urinary IL‐6 levels were not different between rDC and Wt (4.41 ± 0.85 pmol rDC vs. 4.14 ± 1.20 pmol Wt, n=7–10) mice. However, HS feeding increased urinary IL‐6 levels in Wt mice, which was prevented in rDC mice (2.03 ± 0.20 pmol rDC vs. 7.34 ± 2.51 pmol Wt, n=6, p<0.05).These data suggest that baseline BP is modulated by resident innate immune cells specific to the kidney and rDC loss reduces systolic BP; this reduction is maintained during AngII‐hypertension. Notably, our data demonstrate that while systemic IL‐6 levels are unchanged with rDC‐depletion, renal mRNA and urinary IL‐6 levels are decreased during hypertension or HS feeding. Thus together, these data propose a model for rDC‐mediated increases in IL‐6 levels during hypertension or increased salt consumption, altering the pro‐inflammatory milieu and increasing distal sodium reabsorption.Support or Funding InformationNIDDK085097 and Department of Veteran Affairs MERIT Award I01BX002322‐01 to RSH; 2T32DK7656‐21 Emory Renal Division to BMW; R37 DK037963 to DCE;