Thomas M. Coffman

The macula densa (MD) is a distinct cluster of approximately 20 specialized kidney epithelial cells that constitute a key component of the juxtaglomerular apparatus. Unlike other renal tubular epithelial cell populations with functions relating to reclamation or secretion of electrolytes and solutes, the MD acts as a cell sensor, exerting homeostatic actions in response to sodium and chloride changes within the tubular fluid. Electrolyte flux through apical sodium transporters in MD cells triggers release of paracrine mediators, affecting blood pressure and glomerular hemodynamics. In this issue of the JCI , Gyarmati and authors explored a program of MD that resulted in activation of regeneration pathways. Notably, regeneration was triggered by feeding mice a low-salt diet. Furthermore, the MD cells showed neuron-like properties that may contribute to their regulation of glomerular structure and function. These findings suggest that dietary sodium restriction and/or targeting MD signaling might attenuate glomerular injury.

Activation of AT ₁ (type 1 Ang) receptors stimulates cardiomyocyte hypertrophy in vitro. Accordingly, it has been suggested that regression of cardiac hypertrophy associated with renin-Ang system blockade is due to inhibition of cellular actions of Ang II in the heart, above and beyond their effects to reduce pressure overload. We generated 2 distinct mouse lines with cell-specific deletion of AT _1A receptors, from cardiomyocytes. In the first line (C-SMKO), elimination of AT _1A receptors was achieved using a heterologous Cre recombinase transgene under control of the Sm22 promoter, which expresses in cells of smooth muscle lineage including cardiomyocytes and vascular smooth muscle cells of conduit but not resistance vessels. The second line (R-SMKO) utilized a Cre transgene knocked-in to the Sm22 locus, which drives expression in cardiac myocytes and vascular smooth muscle cells in both conduit and resistance arteries. Thus, although both groups lack AT ₁ receptors in the cardiomyocytes, they are distinguished by presence (C-SMKO) or absence (R-SMKO) of peripheral vascular responses to Ang II. Similar to wild-types, chronic Ang II infusion caused hypertension and cardiac hypertrophy in C-SMKO mice, whereas both hypertension and cardiac hypertrophy were reduced in R-SMKOs. Thus, despite the absence of AT _1A receptors in cardiomyocytes, C-SMKOs develop robust cardiac hypertrophy. By contrast, R-SMKOs developed identical levels of hypertrophy in response to pressure overload–induced by transverse aortic banding. Our findings suggest that direct activation of AT ₁ receptors in cardiac myocytes has minimal influence on cardiac hypertrophy induced by renin-Ang system activation or pressure overload.

Background: Prostaglandin E ₂ ( PGE ₂ ) is a major prostanoid with multiple actions that potentially affect blood pressure ( BP ). PGE ₂ acts through 4 distinct E‐prostanoid ( EP ) receptor isoforms: EP 1 to EP 4. The EP 4 receptor ( EP 4R) promotes PGE ₂ ‐dependent vasodilation, but its role in the pathogenesis of hypertension is not clear. Methods and Results: To address this issue, we studied mice after temporal‐ and cell‐specific deletion of EP 4R. First, using a mouse line with loss of EP 4 expression induced universally after birth, we confirm that EP 4R mediates a major portion of the acute vasodilatory effects of infused PGE ₂ . In addition, EP 4 contributes to control of resting BP , which was increased by 5±1 mm Hg in animals with generalized deficiency of this receptor. We also show that EP 4 is critical for limiting elevations in BP caused by high salt feeding and long‐term infusion of angiotensin II . To more precisely identify the mechanism for these actions, we generated mice in which EP 4R loss is induced after birth and is limited to smooth muscle. In these mice, acute PGE ₂ ‐dependent vasodilation was attenuated, indicating that this response is mediated by EP 4R in vascular smooth muscle cells. However, absence of EP 4R only in this vascular compartment had a paradoxical effect of lowering resting BP , whereas the protective effect of EP 4R on limiting angiotensin II–dependent hypertension was unaffected. Conclusions: Taken together, our findings support a complex role for EP 4R in regulation of BP and in hypertension, which appears to involve actions of the EP 4R in tissues beyond vascular smooth muscle cells.

The renal collecting duct (CD), as the terminal segment of the nephron, is responsible for the final adjustments to the amount of sodium excreted in urine. While angiotensin II modulates reabsorptive functions of the CD, the contribution of these actions to physiological homeostasis is not clear. To examine this question, we generated mice with cell-specific deletion of AT _1A receptors from the CD. Elimination of AT _1A receptors from both principal and intercalated cells (CDKO mice) had no effect on blood pressures at baseline or during successive feeding of low- or high-salt diets. In contrast, the severity of hypertension caused by chronic infusion of angiotensin II was paradoxically exaggerated in CDKO mice compared with controls. In wild-type mice, angiotensin II induced robust expression of cyclooxygenase-2 (COX-2) in renal medulla, primarily localized to intercalated cells. Upregulation of COX-2 was diminished in CDKO mice, resulting in reduced generation of vasodilator prostanoids. This impaired expression of COX-2 has physiological consequences, since administration of a specific COX-2 inhibitor to CDKO and control mice during angiotensin II infusion equalized their blood pressures. Stimulation of COX-2 was also triggered by exposure of isolated preparations of medullary CDs to angiotensin II. Deletion of AT _1A receptors from principal cells alone did not affect angiotensin II–dependent COX2 stimulation, implicating intercalated cells as the main source of COX2 in this setting. These findings suggest a novel paracrine role for the intercalated cell to attenuate the severity of hypertension. Strategies for preserving or augmenting this pathway may have value for improving the management of hypertension.

The main actions of the renin–angiotensin system to control blood pressure (BP) are mediated by the angiotensin type 1 receptors (AT ₁ Rs). The major murine AT ₁ R isoform, AT _1A R, is expressed throughout the nephron, including the collecting duct in both principal and intercalated cells. Principal cells play the major role in sodium and water reabsorption. Although aldosterone is considered to be the dominant regulator of sodium reabsorption by principal cells, recent studies suggest a role for direct actions of AT ₁ R. To specifically examine the contributions of AT _1A R in principal cells to BP regulation and the development of hypertension in vivo, we generated inbred 129/SvEv mice with deletion of AT _1A R from principal cells (PCKO). At baseline, we found that BPs measured by radiotelemetry were similar between PCKOs and controls. During 1-week of low-salt diet (P P 1A R on baseline BP and adaptation to changes in dietary salt are negligible, our studies suggest that direct actions of AT _1A R contribute to the initiation of hypertension and epithelial sodium channel activation.

Inappropriate activation of the type 1A angiotensin (AT_1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT_1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT_1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT_1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)–dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely preserved (approximately 80% of control levels) in SMKO mice because of exaggerated activity of the sympathetic nervous system rather than residual actions of AT_1B receptors. In contrast, Ang II–dependent responses in the renal circulation were almost completely eliminated in SMKO mice (approximately 5%–10% of control levels). These findings suggest that direct actions of AT_1A receptors in VSMCs are essential for regulation of renal blood flow by Ang II and highlight the capacity of Ang II–dependent vascular responses in the kidney to effect natriuresis and BP control.

The relationship between dietary salt intake and the associated risk of hypertension and cardiovascular disease is an important public health concern. In this issue of the JCI, a study by Zhang and associates shows that consumption of a high-sodium diet induces expression of cyclooxygenase-2 (COX-2) in macrophages, resulting in enhanced levels of prostaglandin E₂ (PGE₂), autocrine activation of the macrophage E-prostanoid 4 (EP4) receptor, and subsequent triggering of parallel pathways in the kidney and in skin that help dispose of excess sodium. The authors found that blockade or genetic elimination of the COX-2/PGE₂/EP4 receptor pathway in hematopoietic cells causes salt-sensitive hypertension in mice. These studies illuminate an unexpected central role for the macrophage in coordinating homeostatic responses to dietary salt intake and suggest a complex pathophysiology for hypertension associated with NSAID use.