Robin A. Felder

Aldosterone/Mineralocorticoid Receptor Stimulation Induces Cellular Senescence in the Kidney

Recent studies demonstrated a possible role of aldosterone in mediating cell senescence. Thus, the aim of this study was to investigate whether aldosterone induces cell senescence in the kidney and whether aldosterone-induced renal senescence affects the development of renal injury. Aldosterone infusion (0.75 μg/h) into rats for 5 weeks caused hypertension and increased urinary excretion rates of proteins and N-acetyl-β-D-glucosaminidase. Aldosterone induced senescence-like changes in the kidney, exhibited by increased expression of the senescence-associated β-galactosidase, overexpression of p53 and cyclin-dependent kinase inhibitor (p21), and decreased expression of SIRT1. These changes were abolished by eplerenone (100 mg/kg/d), a mineralocorticoid receptor (MR) antagonist, but unaffected by hydralazine (80 mg/liter in drinking water). Furthermore, aldosterone induced similar changes in senescence-associated β-galactosidase, p21, and SIRT1 expression in cultured human proximal tubular cells, which were normalized by an antioxidant, N-acetyl L-cysteine, or gene silencing of MR. Aldosterone significantly delayed wound healing and reduced the number of proliferating human proximal tubular cells, while gene silencing of p21 diminished the effects, suggesting impaired recovery from tubular damage. These findings indicate that aldosterone induces renal senescence in proximal tubular cells via the MR and p21-dependent pathway, which may be involved in aldosterone-induced renal injury.

Renal Dopamine Receptors

Dopamine is an endogenous catecholamine that modulates many functions including behavior, movement, nerve conduction, hormone synthesis and release, blood pressure, and ion fluxes. Dopamine receptors in the brain have been classically divided into D1 and D2 subtypes, based on pharmacological data. However, molecular biology techniques have identified many more dopamine receptor subtypes. Several of the receptors cloned from the brain correspond to the classically described D1 and D2 receptors. Several D1 receptor subtypes have been cloned (D1A, D1B, and D5) and are each coupled to the stimulation of adenylyl cyclase. The D2 receptor has two isoforms, a shorter form, composed of 415 amino acids, is termed the D2short receptor. The long form, called the D2long receptor, is composed of 444 amino acids; both are coupled to the inhibition of adenylyl cyclase. The D3 and D4 receptors are closely related to, but clearly distinct from, the D2 receptor. They have not yet been linked to adenylyl cyclase activity. Outside of the central nervous system, the peripheral dopamine receptors have been classified into the DA1 and DA2 subtypes, on the basis of synaptic localization. The pharmacological properties of DA1 receptors roughly approximate those of D1 and D5 receptors, whereas those of DA2 receptors approximate those of D2 receptors. A renal dopamine receptor with some pharmacological features of the D2 receptor but not linked to adenylyl cyclase has been described in the renal cortex and inner medulla. In the inner medulla, this D2-like receptor, termed DA2k, is linked to stimulation of prostaglandin E2 production, apparently due to stimulation of phospholipase A2. Of the cloned dopamine receptors, only the mRNA of the D3 receptor has been reported in the kidney. The DA1 receptor in the kidney is associated with renal vasodilation and an increase in electrolyte excretion. The DA1-related vasodilation and inhibition of electrolyte transport is mediated by cAMP. The role of renal DA2 receptors remains to be clarified. Although DA1 and DA2 receptors may act in concert to decrease transport in the renal proximal convoluted tubule, the overall function of DA2 receptors may be actually the opposite of those noted for DA1 receptors. Dopamine has been postulated to act as an intrarenal natriuretic hormone. Moreover, an aberrant renal dopaminergic system may play a role in the pathogenesis of some forms of hypertension. A decreased renal production of dopamine and/or a defective transduction of the dopamine signal is/are present in some animal models of experimental hypertension as well as in some forms of human essential hypertension.

Development of Adrenergic and Dopamine Receptors in the Kidney

The mechanism for the age related effects of adrenergic neurotransmitters, including dopamine, on the maturing kidney has not been fully evaluated. Since maturational changes in renal hemodynamics and sodium excretion cannot be entirely correlated with levels of renal or circulating catecholamines, changes at the receptor or postreceptor levels have to be considered.

Chapter 19 - Paracrine Regulation of Renal Function by Dopamine

Classical transmitter ligands evolved about 1000 million years ago. 1 The role of dopamine as a neurotransmitter has evolved with time. In primordial and plant cells, dopamine is present, even though catecholamine signaling is not used. In invertebrate neural systems, dopamine is the pre-eminent catecholamine. In vertebrates, the catecholamine pathway terminates in norepinephrine and epinephrine. 2 Endogenous dopamine was mainly recognized as a precursor to norepinephrine and epinephrine 3 until the late 1950s, when Carlsson demonstrated that dopamine itself had a transmitter role. 4 This finding, for which he was awarded the Nobel Prize in Physiology or Medicine 2000, was revolutionary for the understanding of various central functions of the brain, including memory, learning, drug abuse, cognition, and attention; it has also enlightened us regarding the pathogenesis and treatment of various psychiatric and neurological disorders.

Clinical Testing and Evaluation of Glomerular Function

The kidney performs numerous functions, but only some can be evaluated indirectly in a clinical setting. In many instances, the function of both kidneys are evaluated; in others, the function of each kidney should be determined. The function of specific segments of the nephron can also be evaluated by indirect means. This chapter will deal mainly with clearance methods used to evaluate glomerular filtration rate (GFR), renal plasma flow (RPF) and water and solute excretion. Indirect methods to localize actions at specific nephron segments will also be discussed.

Renal Handling of Sodium during Development

Normally growing term infants remain in positive sodium balance while on widely varying salt intakes (1). However, in healthy preterm infants below 35 weeks gestational age a negative sodium balance resulting in hyponatremia has been observed in the first 1–3 weeks of life (2,3). The negative sodium balance in preterm infants is mainly due to renal sodium wasting exacerbated by inefficient intestinal sodium reabsorption (4). It has been estimated that infants less than 33 weeks gestational age require a minimum of 4–5 mEq sodium/kg/day to offset these losses in the first weeks of life. Al-Dahhan et al reported that supplementations of 4–5 mEq/kg/ day in premature babies prevented hyponatremia, maintained a positive sodium balance, improved early growth, and allowed earlier discharge from the hospital. No adverse effects were seen and supplementation v/as not needed after the second postnatal week (4). In contrast, Lorenz et al showed that very low birth weight infants taking as little as 1.6 mEq/kg/day were able to maintain a normal serum sodium concentration.