Proximal tubular cell

Cadmium is effectively accumulated in the kidneys. When the cadmium concentration exceeds 200 gg/g in the kidney cortex, tubular damage will occur in 10% of the population, and proteins begin to leak into urine (proteinuria). When the concentration of cadmium in the kidney cortex exceeds 300 pg/g, the effect is seen in 50% of the exposed population. Typically, excretion of low-molecular weight proteins, such as beta-microglobulin, is increased, due to dysfunction of proximal tubular cells of the kidney. The existence of albumin or other high-molecular weight proteins in the urine indicates that a glomerular injury has also taken place. The excretion of protein-bound cadmium will also be increased. 

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. 

The lead-induced nephropathy observed in humans and rodents shows a comparable early pathology (Goyer 1993). However, in rodents, proximal tubular cell injury induced by lead can progress to adenocarcinomas of the kidney (see Section 2.2.3.8). The observation of lead-induced kidney tumors in rats may not be relevant to humans. Conclusive evidence for lead-induced renal cancers (or any other type of cancer) in humans is lacking, even in populations in which chronic lead nephropathy is evident. 

Ishido, M.S. Homma-Takeda, C. Tohyama, and T. Suzuki. 1998. Apoptosis in rat renal proximal tubular cells induced by cadmium. Jour. Toxicol. Environ. Health 55A 1-12. 

Fine, L.G. and Sakhrani, L.M. (1986). Proximal tubular cells in primary culture. Mineral Electrolyte Metab. 12 51-57. 

Goligorsky, M.S., Menton, D.M. and Hruska, K.A. (1986). Parathyroid hormone-induced changes of the brush border topography and cytoskeleton in cultured renal proximal tubular cells. J. Membr. Biol. 92 151-162. 

Sakhrani, L.M., Badie-Dezfooly, B., Trizna, W., Mikhails, N., Lowe, A., Taub, M. and Fine, L.G. (1984). Transport and metabolism of glucose by renal proximal tubular cells in primary culture. Amer. J. Physiol. 246 F757-F764. 

Oligonucleotides to the Proximal Tubular Cell of the Kidney Using Macromolecular and Pro-drug Approaches... 

Delivery of Drugs and Antisense Oligonunucleotides to the Proximal Tubular Cell... 

The proximal tubular cell plays a major role in the elimination of both inorganic and organic substrates. The ceUs have two distinct membrane domains. The basolateral membrane is in contact with the blood, and the apical brush-border membrane lines the tubular lumen. 

The mesangial cells of the glomerulus and the proximal tubular cells are the first choice targets for renal drug delivery. Both cell types play a central role in many disease processes in the kidney. 

As a consequence of such noxious triggers, proximal tubular cells respond with the synthesis of a host of inflammatory mediators [20]. Because of this, the proximal tubular cell is a central target for drug delivery. 

To date, only a limited number of studies have focused on drug delivery to the mesangium cell and only a modest degree of selectivity has been obtained in this respect [21,22]. More extensive studies have been performed on targeting drugs to the proximal tubular cell. Therefore, in this chapter, only targeting to the proximal tubular cell will be addressed. 

Targeting of anti-inflammatory and anti-fibrotic drugs to the proximal tubular cell may prevent tubulointerstitial inflammation and scarring secondary to systemic and glomerular infection and proteinuria. Furthermore, tubular drug dehvery may be beneficial during shock, renal transplantation, ureter obstruction, diabetes, proteinuria, renal carcinoma and some tubular defect diseases such as Fanconi and Bartter s s5mdrome. 

In the design of drugs, the usefulness of renal-specific enzymes which enable the site-specific release of the active drug, should be taken into account. The design of kidney-selective prodrugs is based upon the relatively higher amounts of certain enzymes in the proximal tubular cells than elsewhere in the body. 

Alternatively, the pro-drug may be a substrate for brush-border enzymes of the proximal tubular cell, resulting in release of the active drug in the tubular lumen and subsequent reabsorption at distal sites or elimination in the urine. 

The drug-LMWP conjugate is stable in the circulation but after arrival in the kidney, the active drug is released in the catabolically-active lysosomes of the proximal tubular cells (Figure 5.7). 

Figure 5.7. Schematic representation of the mechanism by which drug targeting to the proximal tubular cell of the kidney might be achieved using a low molecular weight protein (LMWP) as a carrier.

Figure 5.10. Accumulation of a radiolabelled LMWP in the lysosomes of the proximal tubular cell. Electron microscope autoradiography of renal proximal tubular cells from a rat injected i.v. with [1251]-tyramine-cellobiose-labelled cytochrome-c, 4 h prior to fixation throngh the abdominal aorta. An intense lysosomal accumulation of the protein is observed in three dark electron-dense lysosomes. A few grains are seen over the apical endocytic apparatus. Part of the luminal brush border is found in the upper right hand corner. Magnification, x 25 000. Unpublished data from E. I. Christensen, Arhus, Denmark, and M. Haas, Groningen, Netherlands.

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]. 

The above described studies show that the renal proximal tubular cell is a good target for antisense therapy [135],... 

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