Renal responses produced by microinjection of the kappa opioid receptor agonist, U50-488H, into sites within the rat lamina terminalis.

Activation of central kappa opioid receptors (KOR) has been demonstrated to produce marked free water diuresis with a concurrent increase in renal sympathetic nerve activity (RSNA). This study investigated the cardiovascular (CV) and renal effects evoked by central activation of KOR in two lamina terminalis sites, the median preoptic area (MPA) and anterolateral division of the bed nuclei of the stria terminalis (BST). Rats anesthetized with urethane alpha-chloralose were instrumented to record mean arterial pressure, heart rate, RSNA, and urine output (V). Rats were infused with isotonic saline (25 µL/min) and urine samples were collected during two 10-min control periods and six consecutive 10-min experimental periods following microinjection of vehicle, U50-448H (U50, KOR agonist) alone or norbinaltorphimine (nor-BNI, KOR antagonist) plus U50. Microinjection of U50 into the BST increased V (peak at 30 min, 84.8 ± 12.9 µL/min) as compared to its respective control, vehicle, or nor-BNI plus U50. This diuretic effect occurred without any significant changes in CV parameters, RSNA, or urinary sodium excretion. In contrast, U50 injection into the MPA significantly increased RSNA (peak at 20 mins: 129 ± 9.9) without increasing the other parameters. This study demonstrated novel sites through which activation of KOR selectively increases V and RSNA. The ability of U50 to increase V without affecting sodium excretion and RSNA raises the possibility that LT neurons could be an important substrate through which drugs targeting KOR could selectively facilitate water excretion in sodium-retaining diseases such as congestive heart failure.

Thiol oxidative stress induced by metabolic disorders amplifies macrophage chemotactic responses and accelerates atherogenesis and kidney injury in LDL receptor-deficient mice.

BACKGROUND: Strengthening the macrophage glutathione redox buffer reduces macrophage content and decreases the severity of atherosclerotic lesions in LDL receptor-deficient (LDLR(-/-)) mice, but the underlying mechanisms were not clear. This study examined the effect of metabolic stress on the thiol redox state, chemotactic activity in vivo, and the recruitment of macrophages into atherosclerotic lesions and kidneys of LDL-R(-/-) mice in response to mild, moderate, and severe metabolic stress. METHODS AND RESULTS: Reduced glutathione (GSH) and glutathione disulfide (GSSG) levels in peritoneal macrophages isolated from mildly, moderately, and severe metabolically-stressed LDL-R(-/-) mice were measured by HPLC, and the glutathione reduction potential (E(h)) was calculated. Macrophage E(h) correlated with the macrophage content in both atherosclerotic (r(2)=0.346, P=0.004) and renal lesions (r(2)=0.480, P=0.001) in these mice as well as the extent of both atherosclerosis (r(2)=0.414, P=0.001) and kidney injury (r(2)=0.480, P=0.001). Compared to LDL-R(-/-) mice exposed to mild metabolic stress, macrophage recruitment into MCP-1-loaded Matrigel plugs injected into LDL-R(-/-) mice increased 2.6-fold in moderately metabolically-stressed mice and 9.8-fold in severely metabolically-stressed mice. The macrophage E(h) was a strong predictor of macrophage chemotaxis (r(2)=0.554, P<0.001). CONCLUSIONS: Thiol oxidative stress enhances macrophage recruitment into vascular and renal lesions by increasing the responsiveness of macrophages to chemoattractants. This novel mechanism contributes at least in part to accelerated atherosclerosis and kidney injury associated with dyslipidemia and diabetes in mice.