Tubular cells tubulitis

The kidney contains the major site of renin synthesis, the juxtaglomerular cells in the wall of the afferent arteriole. From these cells, renin is secreted not only into the circulation but also into the renal interstitium. Moreover, the enzyme is produced albeit in low amounts by proximal tubular cells. These cells also synthesize angiotensinogen and ACE. The RAS proteins interact in the renal interstitium and in the proximal tubular lumen to synthesize angiotensin II. In the proximal tubule, angiotensin II activates the sodium/hydrogen exchanger (NHE) that increases sodium reabsorption. Aldosterone elicits the same effect in the distal tubule by activating epithelial sodium channels (ENaC) and the sodium-potassium-ATPase. Thereby, it also induces water reabsotption and potassium secretion. 

Aldosterone acts on the distal tubule of the nephron to increase sodium reabsorption. The mechanism of action involves an increase in the number of sodium-permeable channels on the luminal surface of the distal tubule and an increase in the activity of the Na+-K+ ATPase pump on the basilar surface of the tubule. Sodium diffuses down its concentration gradient out of the lumen and into the tubular cells. The pump then actively removes the sodium from cells of the distal tubule and into the extracellular fluid so that it may diffuse into the surrounding capillaries and return to the circulation. Due to its osmotic effects, the retention of sodium is accompanied by the retention of water. In other words, wherever sodium goes, water follows. As a result, aldosterone is very important in regulation of blood volume and blood pressure. The retention of sodium and water expands the blood volume and, consequently, increases mean arterial pressure. 

A plot of rate of transport against solute concentration in the tubule (Figure 8.3) shows fm, the tubular transport maximum to be analogous with Vmax for an enzyme, which is a maximum rate of solute transport across tubular cells. Assuming a fixed GFR, the point at which the plotted line begins to deviate from linearity, indicates that the substance exceeds a critical threshold concentration and begins to be excreted in the urine. When the plotted line reaches a plateau indicating that saturation point, that is tm has been reached, the rate of excretion is linear with increase in plasma concentration. The concept of fm as described here for tubular reabsorption applies equally well to carrier-mediated secretory processes. If the fm value for a particular is exceeded for any reason, there will be excretion of that solute in the urine. 

Autoradiographic studies of the kidney have shown the accumulation of AS-ODN to occur almost exclusively in the proximal tubular cells [110,119]. Oberbauer et al. reported that intravenously injected AS-ODN accumulated in proximal tubular cells, and electron microscopy revealed that AS-ODN did accumulate only in the brush border or lysosomal compartment. This implies that the AS-ODNs were not completely degraded after being taken up by the proximal tubule [110]. 

In the isolated perfused kidney model, the artery of the kidney is perfused and urinary samples as well as venous blood samples can be collected to determine the drug concentration. A serious drawback of the model is that isolation and artificial perfusion greatly affect the function of the organ as shown by a dramatic drop in the glomerular filtration rate. Another in-vitro model is the isolated tubule in which samples can be taken from both the luminal and basolateral sites of the tubule [140,141]. The disadvantage of this technique as well as of the isolated kidney model, is that they require specific equipment and expertise and therefore can only be performed in rather specialized laboratories. Experiments using freshly isolated or cultured cells are more simple to carry out [142,143]. Tubular cells can be grown in a po-... 

Figure 12.6 Mechanism of action of mineralocortjcoid receptor antagonists in the collecting tubule. Aldosterone enters the tubular cell by the basolateral surface and binds to a specific mineralocorticoid receptor (MNR) in the cytoplasm. The hormone receptor complex triggers the production of an aldosterone-induced protein (AlP) by the cell nucleus (NUC). The AIP acts on the sodium ion channel (ic) to augment the transport of Na+across the basolateral membrane and in to the cell. An increase in AIP activity leads to the recruitment of dormant sodium ion channels and Na pumps (P) in the cell membrane. AIP also leads to the synthesis of new channels and pumps within the cell. The increase in Na+conductance causes electrical changes in the luminal membrane that favour the excretion of intracellular cations, such as K+and H-h. Spironolactone competes with aldosterone for the binding site on the MNR and forms a complex which does not excite the production of AIP by the nucleus.

Ion transport pathways across the luminal and basolateral membranes of the distal convoluted tubule cell. As in all tubular cells, Na+/K+ ATPase is present in the basolateral membrane. NCC is the primary sodium and chloride transporter in the luminal membrane. (R, parathyroid hormone [PTH] receptor.)... 

These transporters can be responsible for the toxicity of some xenobiotics. For example, the drug cephaloridine is toxic to the kidney as a result of accumulation in the proximal tubular cells, which form the cortex of the kidney. The drug is a substrate for OAT-1 on the basolateral surface and hence is transported into the proximal tubular cells. However, the transport out of these cells from the apical surface into the lumen of the tubule is restricted, probably because of the cationic group on the molecule (Fig. 7.34). The toxicity of cephaloridine is modulated by chemicals that inhibit the OAT-1 and cation transporters. The similar drug cephalothin is not concentrated in the cells and is not nephrotoxic (Table 3.5). See chapter 7 for more details. 

Acute exposure to inorganic lead can cause reversible damage to the kidneys, manifested as tubular dysfunction. Chronic exposure to lead, however, causes permanent interstitial nephropathy, which involves tubular cell atrophy, pathological changes in the vasculature, and fibrosis. The most pronounced changes occur in the proximal tubules. Indeed, lead-protein complexes are seen as inclusion bodies in tubular cells, and the mitochondria in such cells have been shown to be altered with impaired oxidative phosphorylation. Clearly, this will influence the function of the proximal tubular cells in reabsorption and secretion of solutes and metabolites. Consequently, one indication of renal dysfunction is amino aciduria, glycosuria, and impairment of sodium reabsorption. 

Hexachlorobutadiene is a nephrotoxic industrial chemical, damaging the pars recta of the proximal tubule. Initial conjugation with GSH is necessary, followed by biliary secretion and catabolism resulting in a cysteine conjugate. The conjugate is reabsorbed and transported to the kidney where it can be concentrated and becomes a substrate for the enzyme p-lyase. This metabolizes it into a reactive thiol, which may react with proteins and other critical macro molecules with mitochondria as the ultimate target. The kidney is sensitive because the metabolite is concentrated by active uptake processes (e.g., OAT 1), which reabsorb the metabolite into the tubular cells. 

Figure 16-17. Section of rat kidney exposed to toxic chemicals, showing tubular cells in the outer medulla. Also note the appearance of giant epithelial cells on the margin of the tubules.

The effects of aluminofluoride complexes on the kidney were studied using glomerular mesangial cells, proximal tubular cells, and inner medullar collecting tubule cells of rat kidney. 

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