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Background: Racial differences in the predilection to salt sensitivity may arise from different renal growth patterns. To test this idea, we monitored age-dependent telomere attrition rate, reflecting largely the replicative history of somatic cells, in the outer renal cortex and the inner renal medulla of African Americans and Caucasians., Methods: Telomere length, determined by the mean length of the terminal restriction fragments (TRF), was measured in specimens from 58 African-American and 63 Caucasian males, ages 1 day to 71 years., Results: In the outer renal cortex, TRF length attrition rate was significantly slower in African Americans (-0.021 +/- 0.0064 kb/year) than in Caucasians (-0.060 +/- 0.0094 kb/year) (p = 0.0007). In both ethnic groups the TRF length attrition rate was slower in the inner medulla than in the outer renal cortex, but without significant racial differences., Conclusions: The proximal tubule is the most abundant nephron structure in the outer renal cortex. Less proliferative growth of proximal tubular cells in kidneys from African Americans may be one factor explaining the slower age-dependent telomere attrition rate in the outer renal cortex of African Americans than in Caucasians., (Copyright (c) 2004 S. Karger AG, Basel.)

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic adenosine monophosphate dependent, low-conductance chloride channel found on the apical plasma membrane of secretory epithelia. Surprisingly, since cystic fibrosis patients have no kidney phenotype, CFTR is highly expressed in the kidney, present from 12 weeks of gestation in the human metanephric kidney. As well as the mature, full-length, 165-kD wild-type protein (WT-CFTR) associated with renal tubule plasma membranes, intracellular, partially glycosylated forms are also seen in normal kidneys. In addition, a kidney-specific splice variant of CFTR translates a cytoplasmic truncated protein (TNR-CFTR), apparently associated with a specific small endosomal population, and is predominantly expressed in the renal medulla. WT-CFTR and TNR-CFTR show different patterns of developmental regulation, WT-CFTR being the major form expressed early in metanephric development when it is localized at the apical plasma membrane of developing collecting tubules. By contrast, TNR-CFTR expression increases with gestational age, reaching adult levels at 23 weeks. Evidence suggests that WT-CFTR plays a role in chloride secretion into the apical lumen of normal distal tubules. In autosomal dominant polycystic kidney disease, normally targeted CFTR at the apical plasma membrane in association with mislocalized Na-K-ATPase may result in abnormal fluid secretion into cysts. Similar colocalization of WT-CFTR and Na-K-ATPase at the apical plasma membranes is found in collecting tubules during development when it is speculated to play a role in the initiation of opening of the tubule lumen.

This short review summarizes some information concerning what is known about matrix adhesion molecules, focal adhesion proteins, and cell-cell adhesion molecules in normal renal development and cystic diseases of the kidney. The focus is on human nephrogenesis and disease, but utilizes critical information gained from genetically manipulated mouse models. Interestingly, a significant role for the human PKD-1-encoded gene product, polycystin-1, has been found in cell-matrix interactions via integrins during development, and mutations lead to autosomal dominant polycystic kidney disease (ADPKD). Recent studies on human ADPKD have implicated polycystin-1 in the formation of multiprotein complexes containing focal adhesion proteins at the basal cell surface of the normal ureteric bud. Further evidence of a critical role of cell-matrix interactions via focal adhesion complex formation is provided by the development of renal cystic disease in tensin knockout mice.

Three methods were used simultaneously to determine the relationships between the vertical forces exerted on the hooves and the positions of the limbs and hooves at the times of peak vertical forces from 2 horses galloping on a track straightaway. Vertical forces were recorded from an instrumented shoe, fetlock joint motion was measured with an electrogoniometer and the angles of the carpus, fetlock and hoof were determined from slow-motion films. At hoof contact, the mean angles of the carpus and fetlock were 181-182 degrees and 199-206 degrees, respectively. Peak vertical forces on the heel occurred at or near maximum extension of the carpal and fetlock joints. Peak forces on the toe occurred during flexion of the fetlock joint and at mean hoof angles of 28-31 degrees from the horizontal. The mean angles of the hoof from the horizontal at the time of heel contact were 6-7 degrees. Hoof lift occurred at mean carpal angles of 173-174 degrees and mean fetlock angles of 199-200 degrees.

Aging is associated with a decline in renal concentrating ability in response to dehydration-induced arginine vasopressin (AVP) release. To examine target tissue sensitivity, cortical collecting tubules (CCT) were individually microdissected from young (3 months), middle-aged (2-3 years) and old (4-5.5 years) rabbits and subjected to in vitro perfusion analysis and tissue culture of defined epithelial monolayers. Osmotic fluid transport was compared with adenylate cyclase activity and an age-associated decline in both parameters detected in response to increasing doses of AVP. [3H]-AVP binding was unchanged in CCT epithelia of different ages, excluding receptor alterations as the underlying mechanism. Also, hydraulic conductivity measurements of isolated young and old CCT were not significantly different, excluding post-cAMP events as a major mechanism of reduced sensitivity. Effects of cholera toxin and forskolin on hydraulic conductivity and adenylate cyclase activity showed a dramatic decrease in the ability of these compounds to elicit a response in CCT epithelia from old rabbits. It was concluded that alterations in Gs proteins and the catalytic unit of adenylate cyclase-were responsible for the age-associated decline in CCT response to AVP.

The preliminary results of a study to estimate the level of cytosol oestrogen and progesterone receptors in the lower urinary tract are presented. 29 full thickness biopsies were obtained from the vault, trigone and urethra of 9 female surgical patients aged 13-72 years. Cytosol assay for oestradiol-17 beta receptors and progesterone receptors was performed. Oestrogen receptors were present in all 5 urethral specimens examined and with a consistently higher concentration in the middle and distal thirds in comparison to the proximal urethra. In only 1 of the 9 vault specimens and 8 trigone specimens were receptors found and those in small quantities. No progesterone receptors were determined in any of the vault, trigone and urethral specimens examined. The presence of oestrogen receptors in the middle and distal thirds of the human female urethra is strong supportive evidence of the sensitivity of the urethra to oestrogens, and the higher concentration of those receptors in these sites in comparison to the proximal urethra, vault and trigone confirms the common embryological origin of the distal urethra and vagina from the definitive urogenital sinus. The absence of measurable progesterone receptors in all the lower urinary tract specimens examined is discussed.

An assessment of the Urilos System for quantifying urinary incontinence is presented. There was approximate reproducibility of urine loss measurements between nappies in the same pack but under- and over-recordings of up to 25 and 23%, respectively, were observed; when packs of nappies were compared there were differences of up to 68%. Thus, the Urilos System is not, as yet, sufficiently reliable for quantifying incontinence. Other methods of measuring incontinence objectively are discussed and the use of the daily bladder chart is commended.

There was no significant difference between the levels of cytochrome oxidase and malate dehydrogenase in whole liver homogenates or in mitochondria isolated from the livers of 6-month-old and 30-month-old C57/BL mice. Little change with age was found in the cytochemical localisation of either enzyme. There were no significant changes in endogenous, state III or state IV respiration of mitochondria isolated from the livers of young and old mice.

Hepatocytes, endothelial and Kupffer cells were isolated from young adult (3 month) and old (24 month) rat livers and the activities of some plasma membrane, endoplasmic reticulum, mitochondrial, lysosomal and soluble enzymes compared using biochemical and electron microscope cytochemical techniques. Age-associated changes included: a decrease in glucose-6-phosphatase activity both in hepatocytes and sinus lining cells; and increase in alkaline phosphatase in endothelial cells but a decrease in hepatocytes; reduced basal and glucagon-induced adenyl cyclase in hepatocytes and endothelial cells and an increase in the number of hepatocytes with gamma-glutamyl transferase reaction. Cytochemistry showed that heterogeneity may also be characteristic of senescence particularly with regard to hepatocyte glucose-6-phosphatase which was absent in some cells, low in many cells but high in some and gamma-glutamyl transferase which was normally lacking from hepatocytes but localised as large deposits of reaction product on the plasma membranes of occasional cells isolated from old donors.

In the livers from young (3-6 month) and old (30 month) C57/BL mice and BN/Bi rats light microscope histochemistry has shown that enzyme activity is not always distributed evenly throughout the lobule. The mitochondrial enzyme succinic dehydrogenase, the plasma membrane enzyme 5'-nucleotidase and the endoplasmic reticulum enzyme glucose-6-phosphatase showed heavier reaction product in the perioportal regions of the lobule compared with the centrilobular regions. Alkaline phosphatase showed an altered distribution pattern with age: in young livers this was uniform throughout the lobule while in old livers there was enhanced peripoertal activity. Electron microscope cytochemistry showed that this was due to increased numbers of bile canaliculi in this region containing reaction product and to the additional presence of reaction product associated with the microvilli lining the space of Disse.

A case of pagetoid reticulosis is presented. Histopathology showed infiltration of the epidermis by mononuclear cells. Twenty percent of the mononuclear cells showed the presence of lysozyme indicating a histiocytic origin. Electron microscopy confirmed the presence of lymphocytes and histiocytes but these cells were outnumbered by Sézary cells. The presence of large numbers of Sézary cells indicates that pagetoid reticulosis is a cutaneous T-cell lymphoma closely related to mycosis fungoides.

The ultrastructure of perfused livers and of mitochondrial fractions from 6-month-old and 30-month-old C57/BL mice were studied. In old mice the liver cell mitochondria were enlarged and rounded with a light 'foamy', vacuolated matrix, short cristae and a loss of dense granules. Quantitative studies showed a 60% increase in the mean size and an increased proportion of larger mitochondria in intact 30-month-old perfused livers. Endothelial and Kupffer cell mitochondria were smaller than those of the parenchymal cells. Mitochondria in pellets prepared from 6- and 30-month-old livers were rounded and condensed, although there were a few larger and 'foamy' mitochondria in the preparations from old mice. Up to 47% of large mitochondria in the old livers were lost during cell fractionation.

The use of various types of cultured mammalian renal tubular epithelial cells in the study of cell injury has been reviewed. Permanent cell lines, primary explant cultures, monolayers from individually microdissected tubules, isolated cells and organ cultures have been used. In the majority of studies, cultured cells of normal tissue origin have been treated with a noxious agent and alterations in growth, morphology, biochemical and immunological properties studied. Earliest studies examined infection by parasites and bacteria and the effects of plant and bacterial toxins, carcinogens, metabolic and transport inhibitors, cytoskeletal perturbants, general inhibitors of protein, glycoprotein, DNA and RNA synthesis. More recent studies have concentrated on the effects of specific nephrotoxins, such as heavy metals and aminoglycoside antibiotics and of ischemia which have bearing on the pathogenesis of acute renal failure. An additional approach has been to culture diseased renal epithelia of cystic, diabetic or tumor origin and compare their properties with those of normal cultured tubular epithelia. Future studies using cultured renal tubular cells will be valuable in elucidating the cellular and subcellular mechanisms of renal epithelial cell injury in disease.