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OBJECTIVE: Elevated circulating chromogranin A (CHGA) is observed in human hypertension. CHGA is critical for granulogenesis and exocytosis of catecholamine stores from secretory large dense core vesicles (LDCV). This study aims to understand the morphological, molecular and phenotypic changes because of excess CHGA and the mechanistic link eventuating in hyper-adrenergic hypertension. METHODS: Blood pressure and heart rate was monitored in mouse models expressing normal and elevated level of CHGA by telemetry. Catecholamine and oxidative stress radicals were measured. Adrenal ultrastructure, LDCV content and mitochondrial abundance were compared and respiration analyzed by Seahorse assay. Effect of CHGA dosage on adrenal ATP content, electron transport chain components and uncoupling protein 2 (UCP-2) were compared in vivo and in vitro. RESULTS: Mice with excess-CHGA displayed hypertensive phenotype, higher heart rate and increased sympathetic tone. They had elevated plasma catecholamine and adrenal ROS levels. Excess-CHGA caused an increase in size and abundance of LDCV and adrenal mitochondria. Nonetheless, they had attenuated levels of ATP. Isolated adrenal mitochondria from mice with elevated CHGA showed higher maximal respiration rates in the presence of protonophore, which uncouples oxidative phosphorylation. Elevated CHGA resulted in overexpression of UCP2 and diminished ATP. In vitro in chromaffin cells overexpressing CHGA, concomitant increase in UCP2 protein and decreased ATP was detected. CONCLUSION: Elevated CHGA expression resulted in underlying bioenergetic dysfunction in ATP production despite higher mitochondrial mass. The outcome was unregulated negative feedback of LDCV exocytosis and secretion, resulting in elevated levels of circulating catecholamine and consequently the hypertensive phenotype.

Purpose of review The imbalances in the activities of various components of the neurohormonal system that maintain renal homeostasis may have important implications in pathophysiology. This review aims to examine the evidence for disparities between angiotensin II and nitric oxide in acute and chronic kidney diseases. Recent findings Low nitric oxide generation and activity characterize chronic kidney disease, whereas decreasing angiotensin activity is known to be beneficial. High oxygen consumption and hypoxia are thought to play important roles in progression of kidney disease, and angiotensin II and nitric oxide appear to influence oxygen consumption in these models. The common etiologic models of acute kidney injury, such as ischemia, nephrotoxic drug administration, radiocontrast exposure and sepsis, also demonstrate significant imbalances in the activities of angiotensin II and nitric oxide. Summary Disparities between the activities of angiotensin II and nitric oxide are pervasive in a variety of acute and chronic kidney diseases. A better understanding of these interactions and their net effect on renal pathophysiology can lead to therapeutic interventions aimed at preventing or correcting such imbalances.