Uroguanylin and guanylin, which are hormones produced by neuroendocrine cells in the intestine, are activated by the intake of oral NaCl. These hormones then enter the bloodstream and hinder the reabsorption of NaCl and water by the kidneys through the activation of membrane-bound guanylyl cyclase receptors.

Sgk1, a serine/threonine kinase, plays a crucial role in maintaining the balance of NaCl and K+ in the body by regulating their excretion through the kidneys. Studies conducted on Sgk1 knockout mice have demonstrated that this kinase is essential for their survival during severe NaCl restriction and K+ loading. When NaCl is restricted and K+ is loaded, plasma [aldosterone] increases rapidly, leading to a rapid rise in Sgk1 protein expression and phosphorylation. Phosphorylated Sgk1 enhances the reabsorption of Na+ through ENaC channels in the collecting duct. It achieves this primarily by increasing the number of ENaCs in the apical plasma membrane of principal cells and also by increasing the number of Na+,K+-ATPase pumps in the basolateral membrane. Phosphorylated Sgk1 inhibits Nedd4-2, which is a ubiquitin ligase responsible for monoubiquitinylation of ENaC subunits. By inhibiting Nedd4-2, Sgk1 reduces the removal of ENaC channels from the plasma membrane, thus increasing the number of channels available. Sgk1 also facilitates the translocation of K+ channels (ROMK) from an intracellular pool to the plasma membrane, thereby enhancing ROMK-mediated K+ secretion by principal cells. These effects of Sgk1 precede the aldosterone-stimulated increase in the abundance of ENaC, ROMK, and Na+,K+-ATPase, leading to a delayed secondary increase in NaCl and K+ transport by the collecting duct, which occurs after a minimum of 4 hours. Activating mutations in Sgk1 result in elevated blood pressure, likely due to increased NaCl reabsorption by the collecting duct, which leads to an increase in extracellular fluid volume (ECFV) and subsequently blood pressure.

Furthermore, the involvement of uroguanylin and guanylin helps explain why the kidneys exhibit a more pronounced natriuretic response when NaCl is ingested orally compared to intravenous delivery. This response is due to the increase in intracellular [cGMP] caused by these gut-derived hormones.

Catecholamines, specifically norepinephrine released from sympathetic nerves and epinephrine from the adrenal medulla, stimulate the reabsorption of NaCl and water by the proximal tubule, thick ascending limb of the loop of Henle, distal tubule, and collecting duct. Although sympathetic nerves are inactive when ECFV is normal, their activity increases significantly when ECFV decreases, such as after hemorrhage, resulting in enhanced reabsorption of NaCl and water by these nephron segments.

In contrast, dopamine, another catecholamine, is released from dopaminergic nerves within the kidneys and synthesized by cells in the proximal tubule. Dopamine acts in opposition to norepinephrine and epinephrine. Its secretion is stimulated by an increase in ECFV, and it directly inhibits the reabsorption of NaCl and water in the proximal tubule.

Adrenomedullin, a peptide hormone consisting of 52 amino acids, is produced by various organs, including the kidneys. This hormone induces a significant increase in urine production (diuresis) and the excretion of sodium (natriuresis). Its secretion is stimulated by congestive heart failure and hypertension. The primary effect of adrenomedullin on the kidneys is the promotion of an increase in glomerular filtration rate (GFR) and renal blood flow.
Uroguanylin and guanylin are produced by neuroendocrine cells in the intestine in response to oral ingestion of NaCl. These hormones enter the circulation and inhibit NaCl and water reabsorption by the kidneys via activation of membrane-bound guanylyl cyclase receptors, which
Sgk1 (serum glucocorticoid-stimulated kinase), a serine/threonine kinase, plays an important role in maintaining NaCl and K+ homeostasis by regulating excretion of both NaCl and K+ by the kidneys. Studies in Sgk1 knockout mice reveal that this kinase is required for animals to survive severe NaCl restriction and K+ loading. NaCl restriction and K+ loading enhance plasma [aldosterone], which rapidly (in minutes) increases Sgk1 protein expression and phosphorylation. Phosphorylated Sgk1 enhances ENaC-mediated Na+ reabsorption in the collecting duct, primarily by increasing the number of ENaCs in the apical plasma membrane of principal cells and also by increasing the number of Na+,K+-ATPase pumps in the basolateral membrane. Phosphorylated Sgk1 inhibits Nedd4-2, a ubiquitin ligase that monoubiquitinylates ENaC subunits, thereby targeting them for endocytic removal from the plasma membrane and subsequent destruction in lysosomes. Inhibition of Nedd4-2 by Sgk1 reduces the monoubiquitinylation of ENaC, thereby reducing endocytosis and increasing the number of channels in the membrane. Sgk1 induces the translocation of K+ channels (ROMK) from an intracellular pool to the plasma membrane, and thereby enhances ROMK-mediated K+ secretion by principal cells. These effects of Sgk1 precede the aldosterone-stimulated increase in ENaC, ROMK, and Na+,K+-ATPase abundance, which leads to a delayed (>4 hours) secondary increase in NaCl and K+ transport by the collecting duct. Activating polymorphisms in Sgk1 cause an increase in blood pressure, presumably by enhancing NaCl reabsorption by the collecting duct, which increases the ECFV and thereby blood pressure.
increase intracellular [cGMP]. The involvement of these gut-derived hormones helps explain why the natriuretic response of the kidneys to an oral NaCl load is more pronounced than when delivered intravenously.
Catecholamines stimulate reabsorption of NaCl. Catecholamines released from the sympathetic nerves (norepinephrine) and the adrenal medulla (epinephrine) stimulate reabsorption of NaCl and water by the proximal tubule, thick ascending limb of the loop of Henle, distal tubule, and collecting duct. Although sympathetic nerves are not active when ECFV is normal, when ECFV declines (e.g., after hemorrhage), sympathetic nerve activity rises and dramatically stimulates reabsorption of NaCl and water by these four nephron segments.
Dopamine, a catecholamine, is released from dopaminergic nerves in the kidneys and is also synthesized by cells of the proximal tubule. The action of dopamine is opposite that of norepinephrine and epinephrine. Secretion of dopamine is stimulated by an increase in ECFV, and its secretion directly inhibits reabsorption of NaCl and water in the proximal tubule.
Adrenomedullin is a 52–amino acid peptide hormone that is produced by a variety of organs, including the kidneys. Adrenomedullin induces a marked diuresis and natriuresis, and its secretion is stimulated by congestive heart failure and hypertension. The major effect of adrenomedullin on the kidneys is to increase GFR and renal blood flow and