Imbalance of T-Cell Subsets in Angiotensin II–Infused Hypertensive Rats With Kidney Injury

Abstract

Abstract-Blockade of angiotensin (Ang) II is efficient in various renal diseases. Although interest has focused on the hemodynamic changes and reduction of proteinuria, recent studies emphasize the nonhemodynamic effects of Ang II on kidney injury. The aim of this study was to clarify the mechanisms of Ang II on the immune system that alter the balance of helper T-cell (Th) subsets. We used a continuous, Ang II infusion model of rats that develop hypertension, proteinuria, and tubulointerstitial damage, including de novo expression of ␣-smooth muscle actin and loss of endothelial cells. We isolated T cells from the spleen and measured cytokine levels by ELISA systems. Ang II-infused rats showed an increase in the Th1 cytokine ␥-interferon and a decrease in the Th2 cytokine interleukin-4. The same change in cytokine mRNA expression in the spleen and kidney was confirmed by quantitative polymerase chain reaction analysis. Our ELISPOT assay showed an increase in the number of ␥-interferon-secreting T cells by Ang II. To investigate whether these changes were specific effects of Ang II, we treated the model rats with the Ang II receptor blocker (ARB) olmesartan or the nonspecific vessel dilator hydralazine. Administration of the ARB ameliorated disease manifestations and the imbalance in Th subsets, whereas hydralazine did not, despite comparable effects on blood pressure. These results demonstrate a direct role of Ang II in the modification of Th balance. T he renin-angiotensin system has been a target for research on hypertension for a long time. This system plays a crucial role in regulating a variety of renal functions, such as blood pressure (BP) and electrolyte and water homeostasis.

Chronic Hypoxia and Tubulointerstitial Injury

“…Our computer-assisted morphologic analysis demonstrated narrowing and distortion of peritubular capillaries with decreased blood flow and hypoxia in a very early phase in this model, before the development of structural kidney damage (37). In addition, angiotensin II damages endothelial cells directly: Administration of angiotensin II to rats causes the loss of peritubular capillaries, an effect that is ameliorated by receptor blockade (38,39). A second important mechanism of angiotensin II-induced ischemia is inefficient cellular respiration and hypoxia via oxidative stress, which is detailed below.…”

Renoprotective Properties of Angiotensin Receptor Blockers beyond Blood Pressure Lowering

“…This benefit might result from an amelioration of hypoxia, which is known to induce tubulointerstitial injury and an attendant infiltration by inflammatory cells. Alternatively, olmesartan might correct an imbalance between helper T cell subsets followed by an ameliorated tubulointerstitial inflammation, as observed after angiotensin II infusion in another hypertensive kidney injury model (46). Further discussion of the cytokine balance in our model of diabetic nephropathy is beyond our scope.…”

Activation of the Renin-Angiotensin System and Chronic Hypoxia of the Kidney

“…Fibrotic kidneys are devoid of peritubular capillary blood, and the corresponding region becomes hypoxic. Among investigations of this effect, we previously demonstrated the loss of peritubular capillaries in angiotensin IIinfused rats by staining with an endothelium-specific antibody, JG-12 (39). This capillary loss was ameliorated by administration of an angiotensin receptor blocker, olmesartan.…”