Which hormone produced by the kidneys plays a role in the production of red blood cells

Associated locations, glands, organs and hormones: Liver, lungs, kidney, heart, vasculature posterior pituitary, and CNS

There are myriad factors involved in regulation of intravascular dynamics. What ensures survival of the organism is not cardiac output, vascular resistance, or blood pressure per se, but perfusion pressure, which is the net effect of these factors. Perfusion pressure is the pressure that allows for transcapillary delivery of nutrients to cells. With respect to the CNS, it also participates in maintenance of the diurnal consciousness required for the integration of information and decision-making, and the direction of motor movement. It is quite logical then to group the liver, lungs, and kidneys in their endocrine function are part of the corticotropic axis. As discussed above (mineralocorticoid activity), they are integrated into a network of hormones that regulate various aspects of intravascular dynamics beyond water retention.

Angiotensin: Liver-kidney-lungs

Angiotensin is a hormone that has constitutive effects throughout the body that serve the global system. Angiotensin is produced within the liver and excreted into the blood in its inactive form. Renin converts hepatic angiotensin to Angiotensin I. Angiotensin I is converted in the lungs to Angiotensin II.152

Of all corticotropic hormones, Angiotensin II plays the most constitutive and comprehensive role in directly and indirectly regulating the hemodynamic cycle (Fig. 6.19). Its direct effects include an augmentation of sympathetic activity, which improves cardiac output. It vasoconstricts, improving perfusion pressure. It augments tubular reabsorption of sodium, chloride, and water and the excretion of potassium, which improves intravascular volume. Within the CNS, it stimulates thirst and a craving for salt. It also augments lipogenesis.152, 153

Fig. 6.19. Renin-angiotensin-aldosterone system.

(By Soupvector [CC BY-SA 4.0], from Wikimedia Commons.)

Its indirect effects complement its direct effects. It stimulates the excretion of aldosterone,154 whose effects have already been discussed. It stimulates vasopressin, which has three roles: increased vascular tone, antidiuresis (prevents the loss of free water), and relaunching of the adrenal cortex activity by stimulating ACTH in the presence of CRH. Together with vasopressin, angiotensin aids in myocardiac repair.155

The counterbalancing hormones, also within the corticotropic axis, include the following (cf. Tables 6.8 and 6.9):

Table 6.8. Summary of agonistic hydroelectric activity

Location	Factor	Effect
Liver	Angiotensin (AT), AT I	Precursor to AT I and II
Kidney	Renin	Converts AT → AT I
Lung	Angiotensin II	Regulates entire hemodynamic profile: • Direct: Sympathetic sensibilization (hemodynamics), vasoconstriction (vascular tone), water and sodium retention • Indirect: Vasopressin (water retention and vasoconstriction), aldosterone (water and sodium retention)
Adrenal cortex	Aldosterone	Sodium and water retention, potassium and hydrogen loss, central adaptation response
Posterior pituitary	Vasopressin	Water retention (no electrolytes), increased vascular tone, adrenal cortex relaunching
Locus ceruleus	Noradrenalin	Hemodynamics, vascular tone
Adrenal medulla	Adrenaline	Hemodynamics, vascular tone

Table 6.9. Summary of antagonistic hydroelectric activity

Location	Factor	Effect
CNS	Dopamine	Vasodilates renal arteries, increases sodium and water loss
Heart	Atrial natriuretic peptide	Inhibits rennin, aldosterone: stimulates excretion of water and sodium
Vasculature	Prostaglandins Nitric oxide	Vasodilates

●

Heart: Atrial natriuretic factor (ANF). It inhibits aldosterone and renin, and has the opposite effects: excretion of sodium and water.156–158

●

Vasculature: Nitric oxide (NO) and prostaglandins are constitutive molecules and as such are not strictly corticotropic hormones. They are mentioned here because they vasodilate through paracrine effects and as such antagonize the effects of the above-mentioned hormones, and in fact trigger their release beyond a certain point of reduced intravascular pressure.159, 160

●

CNS: Dopamine’s peripheral activity on the kidneys is one of vasodilation, increased production of urine, and increased excretion of sodium.161, 162

BLOOD COMPONENTS

Parathyroid carcinoma

Parathyroid carcinoma is an extremely rare type of cancer that causes severe hyperparathyroidism. Because most cases of parathyroid carcinoma produce PTH, renal (nephrolithiasis, nephrocalcinosis, and polyuria) and skeletal symptoms (bone pain, osteopenia, and pathologic fracture) are common in this disorder. Symptoms in other systems are also seen, including gastrointestinal tract (peptic ulcer and pancreatitis) and central nervous system (fatigue and affection disorder). When parathyroid carcinoma invades to surrounding structures, it may cause paralysis of recurrent laryngeal nerve. 40–70% of patients with parathyroid carcinoma have a palpable neck mass. With proper treatments, the overall survival rate of parathyroid carcinoma is estimated to be 85% in 5 years and 49–77% in 10 years from diagnosis (Goswamy et al., 2016). The prevalence of parathyroid carcinoma is very low (0.005% of all cancers). It typically develops in individuals of 45 to 59 years of age without a difference based on sex. While most cases of parathyroid carcinoma occur sporadically, some are accompanied with syndromic diseases (e.g., MEN1).

Some cases of sporadic parathyroid carcinoma are related to MEN1 or CDC73 mutation, which also cause syndromic diseases of hyperparathyroidism. It is still unclear why some patients with MEN1 or CDC73 mutation develop only parathyroid carcinoma without other neoplasia. In a few cases of parathyroid carcinoma, methylation of the CDC73 promoter has been reported as the mechanism of tumorigenesis (Hewitt et al., 2007).

Other gene abnormalities related to the sporadic form of parathyroid carcinoma include retinoblastoma 1 (RB1), tumor protein P53 (TP53), and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) (Cardoso et al., 2017). RB1 is a well-known tumor suppressor gene that negatively regulates cell cycle progression. Allelic loss of RB1 expression has been reported in more than 85% of cases of parathyroid carcinoma. Likewise, TP53 is a tumor suppressor gene encoding p53, which plays a role in apoptosis, DNA repair, and differentiation in damaged cells. Allelic loss of TP53 has been reported in a case of parathyroid carcinoma. TP53 is never detected in differentiated parathyroid carcinoma, so it is thought to be associated with an undifferentiated type of parathyroid carcinoma. EZH2 encodes the histone methyltransferase that controls gene methylation and transcriptional repression (Vire et al., 2006). EZH2 interacts with beta-catenin and induces nuclear accumulation.

The mutations of other genes (e.g., cyclin D1, adenomatous polyposis coli, glycogen synthase kinase 3 beta, and prune homolog 2) have been reported to be associated with parathyroid carcinoma. MicroRNA may also play a role in the development of parathyroid carcinoma.

Abstract

The myriad physiologic functions of the kidneys are heavily regulated by the endocrine system. While extrarenal hormones exert well-recognized actions in the urinary system, in recent decades a host of intrinsic, renal hormones, with powerful effects on renal hemodynamics, glomerular filtration, and tubular electrolyte and water handling has been identified. Renal microcirculation, glomerular mesangium, and tubular epithelium produce angiotensin II, the natriuretic peptide urodilatin, vasoconstrictors endothelin-1 and urotensin II, and vasodilators adrenomedullin and intermedin. In addition, new details are emerging regarding the complex regulation of renal calcitriol production. The hematopoietic renal hormone erythropoietin has been found to mitigate ischemic injury to the kidneys, heart, and central nervous system. This chapter presents these products of the endocrine kidney and discusses their renal and systemic physiologic functions, their beneficial versus maladaptive contributions to renal diseases, and their potential exploitation to treat clinical disorders of the kidneys and other organs.

Other Benchmarks of Adequacy

Replacement of kidney function entails more than renal excretory function. Physiologists have taught us for several decades that the kidney's responsibility is to maintain the integrity of the internal milieu. Although excretion is a major part of that job, control of electrolyte concentrations, acid-base balance, and calcium-phosphate-magnesium balance must be included. Replacement of renal hormones cannot be ignored, and control of water volume is critical, especially in patients with multi-organ dysfunction. Experience in the outpatient clinic has shown, with respect to small solute control, that renal replacement therapy should be considered only barely adequate. It prevents immediate death from uremia but leaves the patient susceptible to cardiovascular disease, infection, and other complications that are reflected in the high yearly mortality rates. Rates of mortality in patients undergoing dialysis in the ICU are even higher than in outpatients and than in patients in the ICU who do not have kidney failure, suggesting that renal replacement therapy is incomplete. Experience with more frequent and continuous replacement techniques is encouraging, and renal hormone replacement has improved markedly the tolerance of dialysis and has reduced mortality. Additional efforts are needed to search for other renal factors that require replacement and to examine the role of poorly dialyzed larger solutes (e.g., polypeptides) and protein-bound solutes.

1 Introduction

The kidneys are known to elaborate four hormones/enzymes vital to normal physiology and long-term survival in mammals. These four principles are: (A) 1,25-dihydroxyvitamin D3 (1,25D) (synthesized in the proximal convoluted tubule), (B) erythropoietin (produced by peritubular capillary endothelial cells in the proximal convoluted tubule), (C) renin (secreted by granular cells of the juxtaglomerular apparatus), and (D) klotho (synthesized and secreted by the distal convoluted tubule). Each of these hormones has multifaceted actions. For example, 1,25D, via its nuclear vitamin D receptor (VDR), modulates the expression of approximately 1500 genes in numerous cell types, contributing to many of life's most fundamental processes. 1,25D maintains the molecular signaling systems that promote growth (p21), development (Wnt), antioxidation (Nrf2/FOXO), and homeostasis (FGF23) in crucial tissues, while at the same time guarding against malignancy and degeneration. A second hormone, erythropoietin, is essential for production of red blood cells in bone marrow, especially under hypoxic conditions, but also promotes hematopoietic cell survival by attenuating apoptosis. Further, in rats, pretreatment with erythropoietin protects neurons during induced cerebral hypoxia (Siren et al., 2001). Other studies suggest that erythropoietin improves memory, mood, neuronal plasticity, and memory-related neural networks (Adamcio et al., 2008). Thus, erythropoietin appears to affect brain function independent of oxygen delivery for metabolism. Similarly, 1,25D, traditionally considered as a renal hormone acting on intestine, bone, and kidney to recruit calcium for the musculoskeletal system, may also influence the CNS and behavior independent of calcium delivery (Patrick & Ames, 2015). A third kidney principle, the enzyme renin, participates in the renin–angiotensin–aldosterone system (RAAS) that is known to control extracellular volume and arterial vasoconstriction. However, the RAAS is also present in many extrarenal sites (Dzau, 1988), including brain, where it stimulates thirst, as well as promotes secretion of antidiuretic hormone from the neurohypophysis to conserve blood volume. Finally, and somewhat analogously to renin, α-klotho (hereafter referred to as klotho) is an enzymatically active protein with a circulating form that is expressed primarily in the kidneys and brain. Klotho is a multifunctional protein that regulates the metabolism of phosphate, calcium, and 25-hydroxyvitamin D. Klotho also may act as a peptide hormone, although an α-klotho receptor has not been identified to date. Point mutations of the klotho (KL) gene in humans are associated with hypertension and kidney disease, indicating that klotho may be essential to the maintenance of normal renal function (Xu & Sun, 2015). Finally, KL is an aging-suppressor gene, and may also be a tumor suppressor gene. The fact that KL expression is affected by erythropoietin, 1,25D, and the RAAS is noteworthy, suggesting that it may be the ultimate integrator of renal hormone action (Berridge, 2015).

The present chapter focuses on two of these renal hormones, 1,25D and klotho, that oppose each other in a closed endocrine loop. However, although 1,25D and klotho counteract one another with respect to phosphate and vitamin D metabolism, the two principles appear to cooperate locally to mediate the molecular signaling systems that promote growth, development, and antioxidation, as well as maintaining mechanisms that effect calcium transient stabilization and prevent phosphate-precipitated senescence that leads to CNS, cardiovascular, and renal decline. 1,25D exerts actions against neural excitotoxicity (L-type calcium channels) and induces serotonin as a mood elevator to support cognitive function and prosocial behavior. Herein, we develop, and provide supporting data for, a vitamin D/klotho healthspan premise, akin to the “vitamin D phenotypic stability hypothesis” recently proposed by Berridge (2015). His view of 1,25D/klotho signaling is calcium-centric, yet incorporates the antioxidation, anti-inflammatory, and antiproliferation functions of 1,25D and klotho, concepts we introduced in a previous treatise (Jurutka et al., 2013). Berridge (2015) extends his theory to include vitamin D in the prevention of neuropsychiatric disorders, a notion that we have also recently addressed (Kaneko, Sabir, et al., 2015), and update herein. Thus, we present in this chapter a related, renal endocrine-centric premise, arguing that the kidneys are the nexus of health span well beyond their obvious function to eliminate nitrogenous waste and balance electrolytes and water. We contend that renal hormones, including 1,25D and klotho, help prevent fibrosis, ectopic calcification, inflammation, and neoplastic transformation, support central nervous system health, as well as benefit the cardiovascular and cerebrovascular systems to lessen the risk of myocardial infarction and ischemic stroke.

Parathyroid Hormone

Wide variation in serum P concentrations corresponds to few direct regulatory mechanisms. PTH, which has greatest impact on serum P, primarily responds to changes in ionized Ca, not P. P is freely filtered at the glomerulus and presents to the renal tubules in high concentrations. The renal tubule reabsorbs P in both the proximal and distal nephrons. In states of low PTH, renal tubular cells reabsorb up to 95% to 97% of filtered P. In states of high PTH, P reabsorption in the proximal and distal tubules is inhibited, resulting in high urinary P excretion. Although markedly affected by PTH in the usual state, renal tubular cells have altered PTH responsiveness in severe P deficiency or overload. Hence, P is reabsorbed when there is severe P deficiency even in high PTH states, and P is excreted when serum P is high despite low PTH.56

During early postnatal life, whereas renal P response to PTH is blunted, PTH increases tubular Ca reabsorption. Together these actions result in retention of both Ca and P in infants, which is favorable for growth. Maternal smoking during pregnancy negatively influences Ca-regulating hormones, leading to relative hypoparathyroidism in both the mother and newborn and lower PTH and 25-OHD in the smoking mother and newborn despite higher serum P.57

INTRODUCTION

The major function of the kidney is to maintain a stable extracellular milieu, which is achieved through the processes of filtration at the glomerulus, and reabsorption and secretion along the renal tubule. Various intra- and extra-renal mediators control these processes. The variety of circulating and locally released factors that has been identified to potentially influence renal tubular function in health and disease has increased dramatically in recent years, and their number continues to rise, in part due to the rapid developments in the field of proteomics (364).

In this chapter, we focus on the renal actions of selected classical and some novel “renal” hormones. We begin by describing the nature of each hormone, its main site(s) of production, control of its release and, where known, its cell mechanism of action. Next, we discuss the possible effects of these hormones on whole kidney function, specifically sodium and water handling, and their action at the level of the renal tubular cell, and we end by introducing the concept of a renal “intracrine” regulatory system. Because of functional similarities and shared transport properties of renal and intestinal epithelial cells, and the possibility of a physiologically important enterorenal axis, we also describe the effects of hormones that might act on both cell types.

The classical hormones we consider are glucocorticoids and thyroid hormones, followed by the gut-related hormones glucagon and insulin, and then other and more recently described brain–gut peptide hormones (excluding guanylin and uroguanylin, Chapter 19). We will not discuss the renin-angiotensin-aldosterone system (Chapter 13), prostaglandins, kinins (Chapter 15), catecholamines, or the natriuretic peptides (Chapter 34), which are all covered separately and in detail elsewhere.

Vitamin D Status and Serum 1,25-Dihydroxyvitamin D3

Cross-sectional data on serum 25(OH)D and 1,25(OH)2D generated variable results as some studies did or did not reveal a positive correlation between the two metabolites. No correlation is expected when the vitamin D status is sufficient in view of the precursor/threshold status of 25(OH)D. Other studies demonstrate a clear positive correlation, usually indicative of a vitamin D insufficiency status as this indicates that the precursor, 25(OH)D, is the limiting factor for renal hormone production. Still other studies revealed a nonlinear correlation with a positive relation between precursor and hormone at low 25(OH)D levels and a plateau at higher levels. Intervention studies with vitamin D supplementation are the best strategy to define the minimal 25(OH)D level to optimize serum 1,25(OH)2D. The caveat here is that such intervention studies should not be short term as it may take several days or weeks for the vitamin D endocrine system to adapt to a new situation especially the resetting of production of the various hormones responsible for 1,25(OH)2D homeostasis such as PTH and fibroblast growth factor 23 (FGF23). In addition, the dose of vitamin D should be in the physiologic range so as to avoid overwhelming the renal 1α-hydroxylase enzyme system. A study of severely vitamin D-deficient elderly subjects (mean baseline 25(OH)D levels around 5 ng/mL) in Belgium [30] revealed that 2 weeks after vitamin D supplementation serum 1,25(OH)2D increased to the level observed in young adults, whereas mean serum 25(OH)D had only risen to about 15 ng/mL. Several other studies revealed no significant increase in serum 1,25(OH)2D after supplementation with physiologic dosages of vitamin D when baseline 25(OH)D was higher than 14–26 ng/mL [31–34]. Overall this precursor–end product relationship indicates that levels of just 15 ng/mL of 25(OH)D are sufficient for the production of a normal concentration of the end product. In the case of chronic renal failure (CRF) stage III–V, higher intake of vitamin D and concomitant higher levels of 25(OH)D to 30 ng/mL or higher are capable of increasing the initially low levels of 1,25(OH)2D as the renal capacity is now the rate-limiting step [35,36].

Pathophysiology of Hypertension

Multiple systems and physiological mechanisms are involved in maintaining normal blood pressure, with the two primary determinants being cardiac output and total peripheral resistance. Cardiac output refers to the amount of blood flow pumped by the heart each minute and is affected by both heart rate and stroke volume (amount of blood ejected from the heart during each contraction). Increases in either heart rate or stroke volume will result in increased cardiac output and thereby increased blood pressure. Total peripheral resistance refers to the amount of force affecting resistance to blood flow throughout the circulatory system. As blood vessels constrict, resistance to blood flow increases, but as these vessels dilate, peripheral resistance declines. Blood pressure is then affected by changes in cardiac output, total peripheral resistance, or by changes in both cardiac output and total peripheral resistance. Regulation of cardiac output and peripheral resistance is influenced by systems outside of the circulatory system, including the autonomic and central nervous systems and the renal system. For example, increases in the sympathetic branch of the autonomic nervous system result in increased blood pressure and heart rate, whereas increases in the parasympathetic branch of the autonomic nervous system typically result in the opposite effect. Sympathetic activity also leads to reabsorption of salt and water by the renal system, which increases blood pressure. Additionally, sympathetic activity is associated with increased secretion of renal hormones like Angiotensin II and aldosterone that lead to elevated blood pressures. Prolonged sympathetic activity also results in vascular remodeling of blood vessels that results in thickening and hardening of the vessel walls (Heilpern, 2008).

The central nervous system exerts control over other systems involved in blood pressure regulation (e.g., circulatory, autonomic nervous, and renal systems) through feedback processes. For example, baroreceptors, located in the carotid artery and aortic walls, detect pressure changes in the arteries and signal the brain to activate either the sympathetic or parasympathetic nervous system to raise or lower blood pressure, respectively. Sustained elevations of blood pressure that occur in patients with essential hypertension eventually damage various organ systems in the body. Specifically, damage to the heart (e.g., left ventricular hypertrophy (thickening), angina or myocardial infarction, coronary revascularization, and heart failure), the brain (stroke or transient ischemic attack and dementia), the kidney (e.g., chronic kidney disease and renal failure), peripheral arterial disease, and retinopathy may occur in response to sustained elevated blood pressures (Kannel, 1996; Rapsomaniki et al., 2014). This damage occurs mainly as the result of changes in the elasticity of blood vessels. Through exposure to chronically elevated pressures, vessel walls lose elasticity, making them more susceptible to cellular injury. As the body attempts to repair these injuries, cholesterol and fat deposits interact with inflammatory responses to restrict blood flow or occlude it completely.

The negative effects of hypertension extend to cognitive functioning, as individuals with hypertension are more likely to develop dementia or cognitive impairment than persons with normal blood pressures (National Heart, Lung, and Blood Institute, 2004). In particular, hypertension is associated with an increased risk for developing vascular dementia (Sharp et al., 2011). Milder forms of cognitive impairment are also apparent among patients with hypertension, who exhibit decreased performance on tasks measuring attention, reaction time, verbal fluency, and executive function when compared with persons with normal blood pressures (see Waldstein et al., 1991).