Toxicology of the Kidney

Ferdinand Rodriguez, Ferdinand Cohen, Christopher K. Ober, Lynden Archer, Joan B. Tarloff, Lawrence H. Lash, Joan B. Tarloff, Lawrence H. Lash

• Verlag: CRC Press
• Jahr: 2004
• ISBN:
  9781134536511
• Auflage: 3
• Thema: Medicine
• Thema: Nephrology

The kidney plays a vital role in certain endocrine functions. Abnormalities caused by toxic chemicals or other interventions can have profound effects on these functions and consequently, on total functions. Toxicology of the Kidney, Third Edition is updated to reflect the latest research in this field and focuses on the correlation between anatomy

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Clinical Nephrotoxicity and Specific Classes of Nephrotoxicants

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Vasoactive and Inflammatory Substances

Norberto Perico, Marina Noris, and Giuseppe Remuzzi

INTRODUCTION

The functioning of the kidney, at both glomerular and tubular levels, is regulated by a complex network of circulating and locally produced hormones. These hormones comprise a chemically heterogeneous group, which includes proteins, lipids, nucleosides, and amino acid-derived molecules. Besides influencing physiological determinants of renal function, these substances, when produced in excess, may participate through their vasoactive and proinflammatory properties to the pathogenic processes, leading to acute or chronic renal dysfunction. They are also involved in the mechanisms by which drugs and chemicals can cause glomerular and tubular structural and functional changes, both in laboratory animals and in humans.

In this chapter, the physiologic actions of the substances that modulate renal function are reviewed. Where appropriate, recent advances of their roles in the pathophysiology of progressive kidney diseases are emphasized. Moreover, the potential relevance of mechanisms and mediators of renal injury are discussed, including the current state of knowledge on the mechanisms of toxicity by which drugs such as cyclosporine, gentamicin, amphotericin B, nonsteroidal antiinflammatory drugs, and radiocontrast media impair renal function.

THE RENIN-ANGIOTENSIN SYSTEM

Regulation of Renin Production and Secretion

The renin-angiotensin system is a phylogenetically old system. It involves multiple organ systems to control the systemic blood pressure and fluid and electrolyte homeostasis. Renin, a glycoprotein synthesized in the juxtaglomerular apparatus of the kidney, converts its substrate, the α2-globulin angiotensinogen synthesized and released by liver cells, to the decapeptide angiotensin I (Ang I). This conversion is believed to take place in plasma. Angiotensin converting enzyme (ACE), a nonspecific dipeptidyl carboxypeptidase present primarily on endothelial cells, acts on Ang I by cleaving the octapeptide angiotensin II (Ang II) from its carboxy-terminal dipeptide. The major effector of the system is actually Ang II, whose actions include vasoconstriction, stimulation of aldoster-one secretion, increased sodium reabsorption by the macula densa, stimulation of thirst by interacting with sympathetic nerve transmission in the central nervous system, and direct inhibition of renin release in the kidney.

In addition to the conversion of Ang I to Ang II, ACE inactivates two vasodilator peptides, bradykinin and kallidin. Inhibition of ACE thus lowers blood pressure through two mechanisms: prevention of the formation of Ang II and potentiation of the hypotensive properties of bradykinin. The availability of specific inhibitors and antagonists of Ang II receptors has helped in defining the concept that not all the actions of endogenous Ang II are carried out by the circulating form of the peptide. ACE inhibitors control blood pressure for periods of time that greatly exceed their plasma half-lives (Naftilan, 1994).

There is also a discrepancy between the antihypertensive effect of ACE inhibitors and plasma ACE activity. These observations prompted investigators to look for possible local formation of Ang II. The finding that bilateral nephrectomy virtually eliminated plasma renin activity without reducing arterial wall renin concentrations in normotensive and hypertensive rats suggested that the arterial renin concentration was independent of renal renin (Naftilan, 1994). Moreover, isolated and perfused vascular tissues generate Ang II, which could be taken to indicate that all components of the cascade are present in vascular tissues (Naftilan, 1994).

Molecular biology techniques allowed cloning and DNA sequencing of all the components of the renin-angiotensin system, including renin, angiotensinogen, ACE, and the Ang II receptors (Dzau et al., 1988). Renin is expressed in various tissues and organs in the mouse and rat, including vascular tissue, brain, testes, heart, submandibular gland and kidney. Angiotensinogen mRNA is present in the heart and vascular tissue, and angiotensinogen expression has been detected in the vascular smooth muscle cells of the aorta. In vivo autoradiography methods and mRNA have located ACE in the heart, with higher signals in the atria than in ventricles. These studies confirmed earlier immunocytochemical observations that ACE activity can be detected in the endothelial cell layer, and further indicate the importance of an intact endothelium for the local generation of Ang II in the vascular wall.

It recently became clear that the renin-angiotensin system is much more complex than previous research suggested. The new story of reninangiotensin system began in 2000, with the discovery of an enzyme similar to ACE, named ACE2 (Donoghue et al., 2000; Tipnis et al., 2000). ACE2 is expressed predominately in vascular endothelial cells of the heart and kidney. Although both are carboxypeptidases, ACE cleaves two amino acids at a time, whereas ACE2 shortens peptides by only one amino acid. The result is that ACE and ACE2 have different biochemical activities. Therefore, Ang I is thought to be converted to angiotensin 1–9 (with nine amino acids) by ACE2, but to the Ang II (with eight amino acids) by ACE. Angiotensin 1–9 has no known effects and cannot be converted to Ang II by ACE2, but can be converted to angiotensin 1–7 (a blood-vessel dilator) by ACE (Boehm and Nabel, 2002). Therefore, it has been suggested that ACE2 prevents the formation of the vasoconstrictor Ang II. The role of ACE2 in blood pressure control is still unclear. However, studies undertaken in ace2 gene knockout mice showed that loss of ACE2 does not alter blood-pressure homeostasis but does severely impair cardiac function (Boehm and Nabel, 2002; Crackower et al., 2002).

In the kidney, renin is produced and stored in granular juxta-glomerular cells, which are modified aortic smooth muscle cells found in the media of afferent arterioles (Griendling et al., 1993). Genomic analysis of the renin gene identified a single locus in humans and rats, but mice have two renin genes, designed Ren-1 and Ren-2 (Griendling et al., 1993), the latter corresponding to the renin produced in mouse kidney. Renin is synthesized in an inactive precursor form, preprorenin. Cleavage of the signal peptide from the carboxyl terminal of preprorenin results in prorenin, which is also biologically inactive. Subsequent glycosylation and proteolytic cleavage leads to formation of renin, a 37 to 40 kDa molecule. Both prorenin and renin are secreted from juxtaglomerular cells. Because prorenin is the major circulating form, it is postulated that significant conversion of prorenin to renin follows secretion.

Stimulation of renin release by juxtaglomerular cells is mediated by increased intracellular cyclic adenosine monophosphate (cAMP), while a rise in cytosolic free calcium is inhibitory (Kurtz, 1986). Physiologic regulators of renin secretion include the urinary NaCl concentration, sensed by macula densa cells in the distal tubule. Decreased NaCl delivery to macula densa cells stimulates renin secretion, whereas increased urinary NaCl exerts an opposite effect (Lorenz et al., 1993). Changes in luminal Cl concentration alter the rate of Na⁺-K⁺-2Cl^- transport in macula densa cells (Schlatter, 1989). The precise mechanism by which variation in the activity of this transport translates into a signal that regulates renin release by adjacent juxtaglomerular granular cells is not entirely clear. Postulated mediators include adenosine, which inhibits renin secretion through activation of adenosine 1 (A1) receptors on juxtaglomerular cells, and alterations in interstitial osmolality, which may affect renin secretion directly (Lorenz et al., 1993). Experimental evidence also suggests that nitric oxide (NO) produced by macula densa and endothelial cells regulates renin secretion (Lorenz et al., 1993; Sigmon et al., 1992). The activity of the renal sympathetic nervous system is well recognized to control renin secretion. Stimulation of post-junctional β-adrenergic receptors increases renin release, whereas the role of α-adrenergic receptors is controversial (Koppa and DiBona, 1993).

Changes in intrarenal perfusion pressure are associated with alterations in renin release (Hackenthal et al., 1990). Elevation of perfusion pressure inhibits renin release and induces the so-called “pressure natriuresis” phenomenon. It has been postulated that increased renal perfusion pressure elevates intracellular calcium in juxtaglomerular cells to inhibit renin secretion (Hackenthal et al., 1990; Kurtz, 1986). Increased perfusion pressure also stimulates NO production by endothelial cells, which in turn suppresses renin secretion (Lorenz et al., 1993). Conversely, decreased renal perfusion enhances the production of prostacyclin (PGI₂), which increases renin release (Henrich, 1981).

Several endocrine and paracrine hormones regulate renin secretion by the kidney. Beside atrial natruiretic peptide (ANP), inhibitory hormones include vasopressin (AVP), endothelin (ET), adenosine and Ang II, the latter probably being the most physiologically relevant by inhibiting both renin gene expression and peptide secretion in a negative feedback loop (Burns et al., 1993; Hackenthal et al., 1990; Kurtz et al., 1986; Lorenz et al., 1993).

Arachidonate metabolites produced in the kidney also play an important role in renin secretion (Lorenz et al., 1993). Intrarenal infusion of arachidonic acid increases, and indomethacin decreases, plasma renin activity in rabbits (Larsson et al., 1974). Moreover, several studies have confirmed that prostaglandins stimulate and lipoxygenase products inhibit renin release (Heinrich et al., 1990; Lorenz et al., 1993).

Vasoactive Properties of Angiotensin II

Circulating and locally produced Ang II exerts its effects by binding to specific receptors (Siragy, 2002). Recently, two subtypes of Ang II receptors have been described in various tissues, based on their affinity for recently developed Ang II antagonists, namely the nonpeptide biphenylimidazoles, typified by losartan, and the tetrahydroimidapyridines (PD), typified by PD123177 and PD121981, or CGP42H2A, a modified peptide analogue of Ang II (Edwards and Aiyar, 1993; Burnier and Brunner, 1994). Inhibition by losartan characterizes the angiotensin I receptor (AT₁ receptor), whereas the PD compounds and CGP42112A identify the AT₂ receptor. Using inhibitors of these receptor subtypes, it has been shown that the AT₁ receptor is the predominant receptor subtype in the vasculature, liver, and kidney of adult rats, but expression of mRNA for AT₁ receptor has also been found in adrenal gland and lung. cDNA clones for AT₁ receptors have been isolated from mice, rabbits, and humans, and show a high degree of homology with the original rat clone. These nucleotide sequences encode for a 359 amino acid protein that has the seven hydrophobic transmembrane domains typical of G protein-coupled receptors.

The rat and mouse have a second form of AT₁ receptor, the AT_1B receptor, with 96% amino acid homology with the original rat AT₁ receptor (now designed as AT_1A receptor). These receptor sub-types are very similar in ligand specificity and signal transduction mechanisms. Vascular smooth muscle and lung express primarily the AT_1A mRNA, the adrenal and pituitary glands express mainly AT_1B, and kidney expresses both. These two receptor isoforms may differ more in the regulation of their expression than in their functional properties.

The AT₂ receptor is a seven transmembrane receptor with a molecular mass of approximately 41,000 da, but it exhibits only approximately 34% homology with the protein sequence of the AT₁ receptor (Carey et al., 2000). In fetal tissues, the AT₂ receptor is widely expressed, predominantly in areas of mesenchymal differentiation (Siragy and Carey, 2001). In the adult rat, the AT₂ receptor is expressed in the vascular smooth muscle cells of mesenteric vessels (Matrougui et al., 1999). In general, sheep and humans have a much higher level of expression of the AT₂ receptor than rodents. The AT₂ receptor protein is present in the heart, coronary arteries, atrial myocytes, and the ventricular myocardium in rat (Wang et al., 1998b). In humans, AT₂ receptor expression c...