Jane McCausland

Development of the renal interstitium.

Abstract The kidney is derived from two tissue sources and develops through a series of mesenchymal-epithelial transitions and epithelial-mesenchymal interactions to form an epithelial tubular organ embedded in an interstitium derived from mesenchyme. The primary interstitium of the embryonic kidney undergoes significant differentiation to form the adult counterpart whose diverse cells have structural and functional characteristics that relate to their local milieu. Whether the adult interstitial cells retain the capacity to transform to other cell types and thus play a role in pathophysiological conditions appears more and more likely as the plasticity of cells becomes apparent. Besides forming the adult interstitium, the primary interstitium is active in metanephric development, with specific roles in nephron growth and collecting duct growth and arborization. Interruptions to the development of the interstitium or amelioration of its developmental capacity result in severely disrupted kidneys. The development of the renal interstitium is an essential component in the process of renal genesis.

In vivo occupancy of angiotensin II subtype 1 receptors in rat renal medullary interstitial cells.

Angiotensin II receptor binding sites in type 1 interstitial cells in the inner stripe of the outer medulla are readily labeled in vitro by the radioligand but not in vivo after systemic radioligand administration. In anesthetized rats, we investigated if reduced vascular delivery due to angiotensin II-induced renal vasoconstriction or, alternatively, prior occupancy of these sites by endogenous angiotensins modulates angiotensin II subtype 1 receptor binding to renal medullary interstitial cells in vivo using electron microscopic autoradiography. Using 125I-angiotensin II, administered systemically, as a radioligand, binding in control rats occurred predominantly in the glomeruli and proximal tubules, while only low binding was observed in the inner stripe of the outer medulla. Pretreatment of rats with unlabeled [Sar1,Ile8]angiotensin II or with the angiotensin II subtype 1 receptor antagonist losartan before receiving the radioligand completely abolished binding to all sites. Renal vasodilatation induced by sodium nitroprusside or use of the radiolabeled antagonist analogue 125I-[Sar1,Ile8]angiotensin II did not alter binding to the inner stripe. In contrast, chronic salt loading or inhibition of angiotensin-converting enzyme by perindopril significantly increased binding not only to the cortical sites but also to the sites in the inner stripe of the outer medulla. Electron microscopic autoradiographs of the inner stripe detected binding in the interstitial cells only in rats treated with chronic salt loading or perindopril. These results suggest that endogenous angiotensins may modulate binding of circulating angiotensin II to the interstitial cells in vivo, and these angiotensin II receptor-bearing cells are more likely to be more responsive to interstitial angiotensin II than to the circulating hormone.

Angiotensin receptors and development: the kidney.

1 This brief review examines the evidence that angiotensin II (AngII) is essential for kidney development. 2 Several components of the renin‐angiotensin system (RAS) are detected in the foetal kidney early in development. 3 Angiotensin II is essential for normal foetal and neonatal renal function. 4 Angiotensin II receptors transduce important signals leading to growth and development. 5 Angiotensin receptor subtypes show spatial and temporal specificity of localization throughout renal development. 6 Angiotensin converting enzyme (ACE) inhibition or AngII receptor blockade (specifically AT1 subtype blockade) results in functional and structural abnormalities of the developing kidney in both experimental and clinical situations. 7 While chronic postnatal RAS blockade in rats is associated with structural damage to tubules and blood vessels of the kidney, reports differ on whether treatment also affects glomerular induction and growth. 8 In metanephric organ culture, glomerular induction proceeds despite AngII receptor blockade. 9 In summary, the evidence suggests that AngII is not essential for nephron induction and glomerular development in the rat kidney. However, AngII is essential for normal growth and development of renal tubules and vasculature.

ANGIOTENSIN CONVERTING ENZYME INHIBITION IN THE POSTNATAL RAT RESULTS IN DECREASED CELL PROLIFERATION IN THE RENAL OUTER MEDULLA

1. Chronic angiotensin converting enzyme (ACE) inhibition or AT1 antagonism during postnatal development in the rat has been shown to cause renal tubular and vascular damage, particularly in the outer medulla.

Angiotensin II receptor subtypes in the kidney: Distribution and function

Summary: Angirotensin II (AII) is a powerful humoral regulator of body fluid and electrolyte balance and arterial blood pressure. In the kidney, All influences renal haemodynamics and proximal tubular reabsorption of sodium through activation of All that mediate complex signal transduction pathways. Angiotensin II is also implicated in the pathophysiological process of some progressive renal diseases. Pharmacological characterization and molecular cloning of All receptor reveals at least two major subtypes of All receptors, AT1 and AT2, in the kidney and other tissues. the AT1 receptor cDNA encodes a 359 amino acid protein with structure typical of seven transmembrane G‐protein coupled receptors. Two isoforms of AT1 receptor, AT1A and AT1B, are known in rodents, but probably only one occurs in other mammals including humans. the AT2 receptor cDNA, a 363 amino acid protein, shares only 32% identical amino acid residues with AT1 receptor, although it also has a seven transmembrane domain topology. In adult mammalian kidneys, AT1 receptors predominate in the glomerular mesangium, proximal tubular epithelium, renomedullary interstitial cells in the inner stripe of the outer medulla and large preglomerular vessels except those in human and monkey where AT2 receptors predominate. By contrast, in foetal kidneys, AT2 receptors are the major subtype; however, this shows dramatic regulation during development. Physiological studies using AT1 selective antagonists show that the known actions of All on renal haemodynamics, glomerular filtration, and tubular sodium and water transport are mediated by this subtype of All receptors. In addition, AT1 receptors also mediate hypertrophic and mitogenic actions of All on cultured glomerular mesangial cells and proximal tubular epithelial cells, and on extra‐cellular matrix accumulation in animal models of progressive renal diseases. By contrast, blockade of AT2 receptors has no effect on renal haemodynamics, tubular sodium reabsorption or growth properties of All. Overall, All exerts multiple actions in the kidney by interacting with different subtypes of All receptors located on multiple cellular sites.

Glomerular stereology: Why, what and how to measure glomerular structure

Summary: Quantitative methods are frequently used to analyse the structure of renal glomeruli. However, on most occasions, measurements are made on glomerular profiles (the two‐dimensional samples of glomeruli seen in histological sections), and provide little or no information about the structure of whole, three‐dimensional glomeruli. Stereology is the discipline concerned with the quantitative analysis of three‐dimensional structures. With stereology one can estimate the total number of glomeruli in kidneys, as well as mean glomerular volume, the number of cells in glomeruli, and the length and surface area of glomerular capillaries. In addition to providing a means for detecting structural differences between glomeruli from different specimens, stereology provides quantitative structural information that can be correlated with quantitative physiological, biochemical and molecular data. Over the past decade we have witnessed the development of a new generation of unbiased, cost‐efficient stereological methods that are ideally suited to analysing glomeruli. Some of these methods are introduced in this review, and then three recent studies from our laboratories that successfully utilized these methods are described. These studies concerned hypertension, kidney development, and the pathogenesis of focal and segmental glomerulosclerosis.

Prevention of diabetes-induced albuminuria in transgenic rats overexpressing human aldose reductase

Studies using pharmacologic inhibitors have implicated the enzyme aldose reductase in the pathogenesis of albuminuria and diabetic renal disease. However, a clear conclusion is not easily drawn from such studies since these pharmacologic inhibitors have nonspecific properties. To examine further the role of aldose reductase, we have overexpressed the human enzyme in a transgenic rat model. Transgene expression in the kidney was predominantly localized to the outer stripe of the outer medulla, compatible with the histotopography of the straight (S3) proximal tubule. The effect of enzyme overexpression on diabetes-induced renal function and structure was then investigated. Contrary to what may have been anticipated from the previous enzyme inhibition studies, diabetes-induced albuminuria was completely prevented by the overexpression of aldose reductase. No effect of overexpression of aldose reductase on renal structure nor on urinary excretion of β2-microglobulin and N-acetyl-β-d-glucosaminidase was observed in this transgenic rat model. In conclusion, our study strongly suggests that multiple roles for aldose reductase may give it a more complex place in diabetic nephropathy than is currently recognized.

Scanning and transmission electron-microscopic study of peripolar cells in the newborn lamb kidney.

Scanning and transmission electron microscopy were used to study the ultrastructural characteristics and positions of granulated peripolar cells in newborn lamb kidney. Following tissue fixation by vascular perfusion in situ, the vascular pole region of the glomerulus was exposed for examination by scanning electron micoscopy following removal of the glomerular tuft. Peripolar cells were recognized by their surface morphology enabling their quantification and an assessment of the relationship of their position in the renal cortex. The prominent expression of peripolar cells in this species was confirmed. Almost every vascular pole examined revealed peripolar cells (405 out of 407; 99.5%) and thus, throughout the cortex, the distribution of peripolar cells was the same as the distribution of renal corpuscles. Larger, more protruding peripolar cells were observed in the outer cortical renal corpuscles. The numbers of peripolar cells encircling each vascular pole ranged from 1 to 10. There was no correlation between number of granulated peripolar cells at the vascular pole and the position of the renal corpuscle within the renal cortex. As viewed by transmission electron microscopy, organelles of protein synthesis were abundant in the cytoplasm of peripolar cells. Exocytosis of cytoplasmic granules was observed by both scanning and transmission electron microscopy implying that a process of regulative secretion occurs from these cells. The use of ultrastrural techniques has provided evidence supporting the concept that peripolar cells are prominent in the cuff region of each renal corpuscle of the newborn lamb and further-more that peripolar cells in this species most likely have a secretory function.