Page 293 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

260 SECTION | II Organ Toxicity

VetBooks.ir provides the supporting framework for the glomerular long-looped nephrons, dip deeply into the inner medulla;
in these nephrons, the proximal aspect of the ascending
capillaries, and is composed of an extracellular matrix,
limb is thin-walled, becoming thick-walled as the tubule
contractile stellate cells which respond to vasoactive hor-
mones, and phagocytic cells which are involved in local reaches the level of the outer medulla. Countercurrent
immune reactions (Khan and Alden, 2002). The distal exchange mechanisms within the loop result in the reab-
ends of glomerular capillaries merge to form efferent arter- sorption of approximately 20% of filtered water and
ioles that progress further down the nephron and form the 25% of filtered sodium and potassium (Schnellmann,
peritubular capillary network that surrounds the renal 2008). In the thin descending limb, water and interstitial
tubules and helps to drive the countercurrent absorption solutes such as urea and electrolytes are able to freely
mechanisms responsible for concentration of the urine and pass into the tubule. At the level of the thin ascending
regulation of electrolyte balance. The majority of renal limb, the tubule becomes impermeable to water and
blood flow and oxygen is expended in the cortex, making urea, and chloride and sodium ions are actively trans-
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the medulla a relatively hypoxic area of the kidney. ported via Na /K 1 ATPases. The loop of Henle resides
Fluid filtered by the glomerulus enters Bowman’s cap- largely within the poorly oxygenated renal medulla, so
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sule and flows into the proximal renal tubule. The proximal the high oxygen demand of the Na /K ATPases makes
tubule is divided into three segments that differ anatomi- this segment especially susceptible to hypoxic injury
cally and functionally. The most proximal segment, S 1 , (Brezis et al., 1984).
consists of the convoluted portion of the proximal tubule The macula densa is composed of specialized cells
and possesses epithelial cells with tall brush borders, well- located between the end of the thick ascending limb of
developed lysosome systems, and numerous basally located the loop of Henle and the most proximal aspect of the dis-
mitochondria. The S 2 segment extends from the end of the tal tubule. This area is in close proximity to afferent arter-
convoluted segment to the beginning of the straight seg- ioles, allowing for communication between the macula
ment and constitutes a transition segment. S 2 segment epi- densa and afferent arteriole of the same nephron. An
thelia have shorter brush borders, fewer mitochondria and increase in intratubular solute concentration at the macula
fewer lysosomes than cells in the S 1 segment. The S 3 seg- densa results in a feedback signal to the afferent arteriole,
ment encompasses the remaining distal portion of the prox- resulting in vasoconstriction and reduction of glomerular
imal tubule and extends into the outer reaches of the filtration rate (GFR). This feedback mechanism helps pre-
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medulla. Oxygen consumption, Na /K ATPase activity vent massive loss of fluid and solute in the face of
and gluconeogenic capacity are greatest in the first two impaired renal tubular absorption. The proximal-most
segments, while the S 3 segment has higher transport capa- aspect of the renal distal tubule is responsible for reab-
bilities for some compounds, such as ascorbic acid (Castro sorption of most of the remaining intraluminal electrolytes
et al., 2008). The S 3 segment is also the site for metabolic such as sodium and potassium. The remaining segment of
activation of some toxicants. the distal tubule and collecting duct absorb sodium, elimi-
In the proximal tubule, passive reabsorption of water nate excessive potassium and hydrogen ions, and absorb
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and active reabsorption (via Na /K ATPases) of sodium additional water (influenced by antidiuretic hormone) as
occurs. Other solutes reabsorbed by the proximal tubule needed to regulate the volume and composition of the
include potassium, calcium, phosphorus, bicarbonate, glu- urine. Agents that disrupt the osmotic gradient of the
cose, amino acids and proteins, and various xenobiotics, medullary region (e.g., by increasing medullary blood
with each segment having a different range of and capac- flow) can disrupt the ability of the kidney to concentrate
ity for reabsorption. For instance, the S 1 segment is pri- urine. Collecting ducts progressively intersect and anasto-
marily responsible for the reabsorption of bicarbonate, mose toward the renal papilla and ultimately empty into
glucose, amino acids and low molecular weight proteins. the renal calyx, renal pelvis, or ureter, depending on spe-
The proximal tubule ultimately reabsorbs 60% 80% of cies. Peristaltic action of the ureter propels urine toward
solute and water filtered by the glomerulus. Excretory the urinary bladder for temporary storage and elimination.
functions of the proximal tubule include the active secre- In addition to its role in regulation of waste excretion
tion of weak organic anions and cations. The proximal and water/electrolyte balance, the kidney secretes a vari-
tubular epithelium possesses cytochrome P450-dependent ety of hormones and regulatory peptides vital for normal
mixed function oxidases capable of metabolizing a variety systemic homeostasis. Secretion of erythropoietin by renal
of endogenous compounds and xenobiotics. Agents that peritubular interstitial cells promotes red blood cell for-
are bioactivated to toxic metabolites (e.g., acetaminophen) mation; significant chronic renal disease is often associ-
can induce proximal renal tubular injury. ated with anemia due to decreases in erythropoietin
Filtrate passes from the proximal tubule into the loop secretion. Renin secreted from the juxtaglomerular cells
of Henle, which has a thin-walled descending limb and a increases systemic and renal blood pressure and aldoste-
thick-walled ascending limb that extends to the level of rone release. Prostaglandins (PGs) and prostacyclin are
the outer medullary region. Some nephrons, termed produced by a variety of renal cells and aid in regulation