Altered ATP-sensitive P2 receptor subtype expression in the Han:SPRD cy/+ rat, a model of autosomal dominant polycystic kidney disease

The effects of extracellular ATP on fluid secretion and reabsorption by renal epithelial cells, as well as its known effects on cell proliferation and death, are potentially important contributory factors in the development and growth of renal cysts. In this study, we have investigated the protein and mRNA expression of several P2Y receptor subtypes (P2Y(1,2,4,6)), as well as the P2X(5) and P2X(7) receptors, in kidney tissue from the Han:SPRD (cy/+) rat model of polycystic kidney disease. All of the P2Y receptors tested for, and the P2X(5) and P2X(7) subtypes, were located on the cyst-lining cells of Han:SPRD (cy/+) rat polycystic kidneys; most immunostaining was cytosolic and we could not confidently localize it to one or other membrane. However, the staining pattern for P2Y(6) was uniquely granular when compared with the other P2 receptors. P2Y(2) and P2Y(6) receptor mRNA was increased in both homozygote (cy/cy) and heterozygote (cy/+) rat kidneys when compared with unaffected littermates. The protein levels of P2Y(2) and P2Y(6) receptors were also increased, being undetectable or at a low level, respectively, in control tissue. Finally, P2X(7) receptor mRNA was increased in cy/+, but not in cy/cy rat kidneys. Our results show that a number of P2Y receptor subtypes, as well as the P2X(5) and P2X(7) receptors, are clearly expressed in cyst-lining cells in the Han:SPRD (cy/+) rat model of renal cystic disease. Furthermore, P2Y(2) and P2Y(6) receptor mRNA and protein levels are markedly increased in cystic rat kidneys compared with normal rats of the same genetic background. Thus, the most consistent findings were an increase in the expression of P2Y(2), P2Y(6) and P2X(7) receptors in cystic tissue. Given the widely reported effects of stimulating these P2 receptor subtypes in epithelial and other renal cells, they could contribute to the development and growth of renal cysts: extracellular ATP and its products 'trapped' in cyst fluid may activate P2 receptors expressed by cyst-lining cells, causing cyst expansion from increased fluid secretion and/or reduced reabsorption, as well as an increase in cell turnover (re-modeling).     

Histogenesis of the renal cysts in adult (autosomal dominant) polycystic kidney disease: a histochemical study

We studied the kidneys from ten patients with adult (autosomal dominant) polycystic kidney disease (APKD) stained with lectins specific for different segments of the nephron on 20 cysts from each case (ranging in size from 0.1 to 1.3 cm in nine cases and from 1.5 to 6 cm in one case). The epithelium of all cysts with positive reactivity (Arachis hypogaea and epithelial membrane antigen) was of collecting duct origin. Many cysts remained unstained. Cysts of proximal tubule origin could not be identified using the specific lectin Lotus tetragonolobus. Focal epithelial hyperplasia appeared in the collecting duct cysts. Cysts surrounded by smooth muscle were frequent and considered to be of collecting duct origin. One case had glomerular cysts. We conclude that the cysts of APKD are principally of collecting duct origin.     

Immunohistochemical localization of atrial natriuretic peptide in the developing and adult mammalian kidney

The discovery, within the last decade, of atrial natriuretic peptide (ANP), a family of peptides with natriuretic/diuretic and vasorelaxant properties, has prompted much research into the mechanisms and sites of action of ANP within the kidney. In the present study, ANP was localized in the kidneys of several mammalian species by immunohistochemical techniques (1) to identify possible sites of synthesis; (2) to compare the localization of ANP to known physiological effects; (3) to determine species differences, if any, in ANP localization; and (4) to study the development of ANP immunoreactivity in the fetal and neonatal rat kidney. Using an antibody against rat ANP IV, ANP was localized exclusively on the proximal convoluted tubule (PCT) brush border and within intercalated cells of the outer medullary and cortical collecting tubules and ducts of adult mouse, rat, pig, monkey, and human kidneys. The development of ANP immunoreactivity paralleled the differentiation and maturation of collecting duct epithelium in rat fetal kidney. Atrial natriuretic peptide found within intercalated cells of the cortical and outer medullary collecting ducts may be the result of endogenous synthesis and, following secretion, may be available to receptors in the inner medullary collecting ducts.     

The structural organization of the kidney of Typhlonectes compressicaudus (Amphibia, Gymnophiona)

Summary The structural organization of the kidney ofTyphlonectes compressicaudus (Amphibia, Gymnophiona) was studied by light microscopic (LM) examination of serial paraffin and semithin Epon sections. The kidney is slender and quite long and has a mesonephric segmental construction; the excretory duct (Wolffian duct), running along the lateral side of the kidney, segmentally receives the terminal trunks of the collecting duct system. The nephron has the following parts: renal corpuscle, neck segment, proximal tubule, intermediate segment, distal tubule and connecting tubule. The distal tubule is located in a ventromedial (central) zone of the kidney; all other tubular segments lie in a dorsolateral (peripheral) zone. The renal corpuscles are found at the border between these two zones.The renal corpuscle is very large; its urinary pole faces the peripheral zone. A small proportion of neck segments receive either a nephrostomal duct or a blind branch. The proximal tubule is a thick, highly convoluted tubule. The intermediate segment is ciliated and makes a few coils. The distal tubule is composed of three portions: a highly convoluted part in the central zone, subsequently an attachment site with the renal corpuscle and a short postattachment-part. The connecting tubule and the collecting duct have a heterogeneous epithelium consisting of light and dark cells. The collecting duct is distinguished by dilated intercellular spaces. The Wolffian duct has a pseudostratified epithelium.The present study correlates the course and segmentation of the renal tubule ofTyphlonectes. The tubule has three major convolutions. The first occurs in the proximal tubule in the peripheral zone; the second is established by the distal tubule and occurs in the central zone; the third is formed by the connecting tubule and is found in the peripheral zone.Research fellow of the Alexander von Humboldt foundation: home address: Department of Anatomy, Faculty of Medicine, University of Tokyo, Tokyo 113, Japan     

Aquaporins in the kidney: from molecules to medicine.

The discovery of aquaporin-1 (AQP1) answered the long-standing biophysical question of how water specifically crosses biological membranes. In the kidney, at least seven aquaporins are expressed at distinct sites. AQP1 is extremely abundant in the proximal tubule and descending thin limb and is essential for urinary concentration. AQP2 is exclusively expressed in the principal cells of the connecting tubule and collecting duct and is the predominant vasopressin-regulated water channel. AQP3 and AQP4 are both present in the basolateral plasma membrane of collecting duct principal cells and represent exit pathways for water reabsorbed apically via AQP2. Studies in patients and transgenic mice have demonstrated that both AQP2 and AQP3 are essential for urinary concentration. Three additional aquaporins are present in the kidney. AQP6 is present in intracellular vesicles in collecting duct intercalated cells, and AQP8 is present intracellularly at low abundance in proximal tubules and collecting duct principal cells, but the physiological function of these two channels remains undefined. AQP7 is abundant in the brush border of proximal tubule cells and is likely to be involved in proximal tubule water reabsorption. Body water balance is tightly regulated by vasopressin, and multiple studies now have underscored the essential roles of AQP2 in this. Vasopressin regulates acutely the water permeability of the kidney collecting duct by trafficking of AQP2 from intracellular vesicles to the apical plasma membrane. The long-term adaptational changes in body water balance are controlled in part by regulated changes in AQP2 and AQP3 expression levels. Lack of functional AQP2 is seen in primary forms of diabetes insipidus, and reduced expression and targeting are seen in several diseases associated with urinary concentrating defects such as acquired nephrogenic diabetes insipidus, postobstructive polyuria, as well as acute and chronic renal failure. In contrast, in conditions with water retention such as severe congestive heart failure, pregnancy, and syndrome of inappropriate antidiuretic hormone secretion, both AQP2 expression levels and apical plasma membrane targetting are increased, suggesting a role for AQP2 in the development of water retention. Continued analysis of the aquaporins is providing detailed molecular insight into the fundamental physiology and pathophysiology of water balance and water balance disorders.     

The structure of the kidney from the freshwater teleost Carassius auratus

Summary The structure of the kidney of the crucian carp (Carassius auratus; a freshwater teleost, Cypriniformes) was studied by means of reconstruction from serial paraffin and semithin sections. In C. auratus, the Wolffian duct traverses the entire kidney. At various levels collecting ducts of different length and thickness join the Wolffian duct at right angles. Each collecting duct accepts a large number of connecting tubules, which are established by the joining of many nephrons. A regular pattern concerning the distribution of nephrons and the fusion of renal tubules is not apparent. Four segments have been distinguished in renal tubules; 1) proximal tubule, 2) distal tubule, 3) connecting tubule and 4) collecting duct. A neck and an intermediate segment are absent. The proximal tubule is established by proximal tubule cells which bear a brush border and have a conspicuous apical cytoplasmic rim containing few cell organelles, ciliated cells, mucous cells and dark cells. In the first part of the proximal tubule the brush border and the apical cytoplasmic rim of proximal tubule cells are well developed. Ciliated cells are interposed between proximal tubule cells, decreasing in number toward the end of this part. In the second part ciliated cells are absent and dark cells are numerous. In the third part the brush border and the apical cytoplasmic rim of proximal tubule cells are scarcely developed. Ciliated cells reapear and increase in number toward the distal tubule. The distal and connecting tubule are similar in epithelial structure. Connecting tubules are joined distal tubules and thus they belong to two or more nephrons. The main cells of distal and connecting tubules contain abundant mitochondria, but have no brush border. The connecting tubule becomes a collecting duct before joining the Wolffian duct. The main cells of collecting ducts are characterized by division of their cytoplasm into a dark apical half and a light basal half.     

The distribution and function of aquaporins in the kidney: resolved and unresolved questions

The membrane water channel aquaporin (AQP) family is composed of 13 isoforms in mammals, eight of which are reportedly expressed in the kidney: AQP1, 2, 3, 4, 6, 7, 8, and 11. These isoforms are differentially expressed along the renal tubules and collecting ducts. AQP1 and 7 are distributed in the proximal tubules, whereas AQP2, 3, and 4 occur in the collecting duct system. They play important roles in the reabsorption of water and some solutes across the plasma membrane. In contrast to other aquaporins found in the kidney, AQP6, 8, and 11 are localized to the cytoplasm rather than to the apical or basolateral membranes. It is therefore doubtful that these isoforms are directly involved in water or solute reabsorption. AQP6 is localized in acid-secreting type A intercalated cells of the collecting duct. AQP8 has been found in the proximal tubule but its cellular location has not yet been defined by immunohistochemistry. AQP11 seems to be localized in the endoplasmic reticulum (ER) of proximal tubule cells. Interestingly, polycystic kidneys develop in AQP11-null mice. Many vacuole-like structures are seen in proximal tubule cells in kidneys of newborn AQP11-null mice. Subsequently, cysts are generated, and most of the mice die within a month due to severe renal failure. Although ER stress and impairment of polycystin-1, the product of the gene mutated in autosomal-dominant polycystic kidney disease, are possible causes of cystogenesis in AQP11-null mice, the exact mechanism of pathogenesis and the physiological function of AQP11 are yet to be resolved.     

Localization and possible function of P2Y(4) receptors in the rodent retina

Extracellular ATP acts as a neurotransmitter in the retina, via the activation of ionotropic P2X receptors and metabotropic P2Y receptors. The expression of various P2X and P2Y receptor subtypes has been demonstrated in the retina, but the localization of P2Y receptors and their role in retinal signaling remains ill defined. In this study, we were interested in determining the localization of the P2Y(4) receptor subtype in the rat retina, and using the electroretinogram (ERG) to assess whether activation of these receptors modulated visual transmission. Using light and electron microscopy, we demonstrated that P2Y(4) receptors were expressed pre-synaptically in rod bipolar cells and in processes postsynaptic to cone bipolar cells. Furthermore, we show that the expression of P2Y(4) receptors on rod bipolar cell axon terminals is reduced following dark adaptation, suggesting receptor expression may be dependent on retinal activity. Finally, using the electroretinogram, we show that intravitreal injection of uridine triphosphate, a P2Y receptor agonist, decreases the amplitude of the rod PII, supporting a role for P2Y receptors in altering inner retinal function. Taken together, these results suggest a role for P2Y(4) receptors in the modulation of inner retinal signaling.     

Purinergic signalling to rat ovarian smooth muscle: changes in P2X receptor expression during pregnancy

The expression of P2X and P2Y receptor subtypes in the smooth muscle of the rat ovary during the oestrus cycle and pregnancy was examined using immunohistochemistry. RT-PCR studies of P2X receptor mRNA were also carried out. In the non-pregnant rats, P2X2 receptor protein was dominant in the smooth muscle of perifollicular rings and blood vessels. P2X1 protein expression was seen on vascular smooth muscle too, but little, if any, was present on perifollicular smooth muscle. No changes in P2X1 or P2X2 receptor expression were seen during the oestrous cycle. During early and mid-late pregnancy, there was a switch from P2X2 to P2X1 receptor protein expression in the smooth muscle of the perifollicular ring; P2X1 receptors were also more prominently expressed than P2X2 receptors on ovarian vascular smooth muscle in non-pregnant animals, but during late pregnancy the expression of P2X2 receptors was found to equal that of the P2X1 receptors. There was a return to non-pregnant P2 receptor subtype distribution 2 days after birth. Ovarian vascular and perifollicular smooth muscle showed immunoreactivity for P2Y1, but not for P2X3-7, P2Y2 or P2Y4 receptors. P2Y1 receptor expression in ovarian smooth muscle of both blood vessels and follicular rings did not show significant changes during the oestrus cycle or pregnancy. RT-PCR studies indicated that P2X1 and P2X2 receptor mRNA was present in the ovary during pregnant and non-pregnant conditions. P2X4-6 receptor mRNA was also present in all stages studied, however no immunostaining showing receptor protein for these subtypes was seen on the ovarian sections examined. In summary, purinergic signalling to ovarian perifollicular smooth muscle changed from P2X2 to P2X1 receptors during pregnancy, while there was an increase in P2X2 receptor expression on vascular smooth muscle.     

Morphological and morphometrical study of the kidney of the male tropical lizard Tropidurus torquatus

A morphological and morphometrical study of the adult male Tropidurus torquatus kidney was undertaken. The nephron is composed of the following segments: renal corpuscle, neck segment, proximal convoluted tubule, intermediate segment, and distal tubule. The nephron is continued into the collecting duct and sexual segment. A large number of ciliated cells in the intermediate segment, the presence of 2 kinds of cells in the collecting ducts and a well developed permanently retained sexual segment were recorded as special features of this organ. The components of the renal parenchyma had the following relative volumes: proximal convoluted tubule = 56.4%, intermediate segment = 5.1%, distal tubule = 13.0%, collecting duct = 5.2%, and sexual segment = 11.6%.     

Mechanism of increased tubular Na-K-ATPase during streptozotocin-induced diabetes

Since the mechanisms responsible for stimulation of kidney Na-K-ATPase during streptozotocin-induced diabetes are unknown, we studied the possible role(s) of kidney hyperfiltration and hypertrophy and of hyperaldosteronism on Na-K-ATPase induction. For this purpose, we studied the relationship between Na-K-ATPase activity in individual nephron segments and alterations of glomerular filtration rate during the early phase of diabetes. Within 2 days after streptozotocin administration, Na-K-ATPase activity markedly increased in the proximal convoluted tubule, medullary thick ascending limb and cortical and outer medullary collecting tubule, but not in the proximal straight tubule, cortical thick ascending limb and distal convoluted tubule. Streptozotocin administration also markedly enhanced the glomerular filtration rate but only after 4 days following initiation of treatment. Changes in Na-K-ATPase were specific since the activity of adenylate cyclase, another marker of basolateral membranes, was not altered. Finally, when animals were adrenalectomized prior to streptozotocin treatment, Na-K-ATPase stimulation was curtailed in the collecting tubule but not in more proximal segments. These results suggest that diabetes alters Na-K-ATPase activity in specific nephron segments independent of alterations of glomerular filtration rate and of kidney hypertrophy, and that the stimulation of collecting tubule Na-K-ATPase is secondary to hyperaldosteronism.     

Purinergic receptors influence the differentiation of human mesenchymal stem cells

Adult stem cells, including adipose tissue-derived mesenchymal stem cells (MSCs) or ectomesenchymal dental follicle cells (DFCs), attract considerable attention for their potential to differentiate into lineages, which are of major interest in the field of Regenerative Medicine. Purinergic receptors exert a wide range of biological actions in many cell and tissue types through extracellular nucleotides. Little is known about P2 receptors in adult stem cells and changes in their expression levels during differentiation. All known P2 receptors have been investigated, and a variety of P2X and P2Y receptor subtypes were detected in MSCs. Studies investigating intracellular calcium levels on receptor stimulation demonstrated that the found P2 receptors are metabolically active. Interestingly, up- or downregulation of several P2 receptor subtypes at gene and protein level was observed during adipogenic and osteogenic differentiation, and the effect on differentiation was directly influenced by both the application of agonists/antagonists and apyrase-induced nucleotide cleavage. Here, we show for the first time that the combination of several P2 receptors plays a role in the differentiation of adult stem cells. The expression pattern of the P2 receptors, as well as their fate in differentiation, varies in stem cells of mesenchymal origin if compared with stem cells of ectomesenchymal origin. The subtypes P2X6, P2Y4, and P2Y14 seem to be pivotal regulators in MSC commitment, as they are regulated in both adipogenic and osteogenic differentiation of adipose tissue-derived stem cells and DFCs. These findings provide new insights into the differentiation processes and might reveal novel options to influence stem cell fate in future applications.     

硒酸锌金属自显影技术检测游离锌离子在小鼠肾脏的分布

目的研究游离锌离子在小鼠肾脏的定位分布。方法应用硒酸锌金属自显影技术(ZnSeAMG)检测小鼠肾脏内的游离锌离子分布。结果游离锌离子在肾脏内分布广泛,皮质中有大量AMG反应阳性颗粒,髓质中的AMG阳性颗粒较少。其中,近曲小管、远曲小管、近直小管和远直小管上皮细胞近腔侧均分布有大量的棕黑色AMG阳性颗粒,肾小体、细段和集合管上皮细胞中AMG阳性颗粒较少。结论小鼠肾脏内含有丰富的游离锌离子,锌离子可能参与肾脏的功能。     

Histology of the kidney and urinary bladder of Siphonops annulatus (Amphibia-Gymnophiona)

The histology of the kidney and urinary bladder of Siphonops annulatus was studied by light microscopy in semithin sections of tissue embedded in hydrophilic resin. The kidney's nephron comprises the renal corpuscle, neck segment, proximal tubule, intermediate segment, distal tubule and collecting tubule. Nephrostomes are present. This structure, the neck segment, and intermediate tubules present long cilia, and probably play important roles in the propulsion of the peritoneal fluid and glomerular filtrate. The proximal tubule cells possess loosely packed microvilli and contain abundant polymorphic granules and vesicles that assume the aspect of lysosomes in different stages of intracellular digestion. The distal tubules are characterized by large, vertically disposed mitochondria assuming the aspect of ions transporting cells. The urinary bladder is lined with a transitional epithelium, whose aspect varies according to the quantity of urine.     

Recent structure-function relationships in normal and injured mammalian kidneys

Recent investigations have been aimed at understanding the ultrastructural-functional relationships within the kidney at organ, tubule, subcellular, and molecular levels. This has led to a redefinition and more precise segmentation of the renal tubule. For example, the connecting piece between distal tubule and collecting system has now been established. The use of immunocytochemical techniques, such as fluorescence, ferritin- or peroxidase-labelled immunoglobulin methods, has made it possible to identify proteins in the kidney especially in renal corpuscles. Two major noncollagenous glycoproteins, fibronectin and laminin, have now been identified in the glomerulus. The glycosaminoglycan, heparan sulfate, has been localized to the glomerular basement membrane and is thought to play an important role in charge perm-selectivity during glomerular filtration. Subtle changes in glomerular podocyte or endothelial cell structure are postulated by some to play a role in the pathogenesis of acute renal failure. The role of the mesangial cell in glomerular function is being studied in situ in homogeneous cell populations. These cells are capable of prostaglandin production and can contract in response to hormonal stimulation. The intimate positioning of short- and long-looped nephrons in the renal medulla and the unique nature of the pelvic epithelium correlates well with the purported role of urea recycling in the urinary concentrating mechanism. Determination of elemental concentration of soluble substances in various renal cell and extracellular compartments have been made using freeze-hydrated and freeze-dried cryosections of kidney tissue. The medullary and cortical ascending thick limbs of the distal tubule are morphologically and functionally distinct regions. Their response to hormonal stimulation and their enzymatic activities are quite different. Morphological studies of the collecting duct have provided new insight into the role this segment of the uriniferous tubule plays in fluid and electrolyte transport and urinary acidification.     

Developmental expression and functional significance of Kir channel subunits in ureteric bud and nephron epithelia

Kir channel subunit expression during development of the rat collecting-duct epithelium was quantified by RT-PCR of primary monolayer cultures. mRNAs of the vascular-type K(ATP) (K(NDP)) channel-forming subunits Kir6.1/SUR2 were highly expressed in early ureteric bud generations (embryonic day E14) and downregulated thereafter, while Kir1.1b (ROMK2) mRNA increased fourfold during cortical collecting duct (CCD) maturation. As assessed by immunohistochemistry, Kir6.1 protein was abundant in the apical and basolateral plasma membranes of early ureteric buds and trunks (E15 to postnatal day P1), downregulated thereafter and not detectable in CCD and outer medullary collecting ducts (OMCD) (P7). During nephron development, Kir6.1 protein was expressed ubiquitously on plasma membranes of early nephron stages from mesenchymal condensations to S-shaped bodies. After fusion of nephron and CCD, Kir6.1 protein was restricted to the apical membrane of proximal tubule. The Kir6/SUR2 channel opener, pinacidil (100 microM/2 days), increased tubulogenesis in organ culture by a factor of 3. Cell proliferation of human embryonic kidney cells (HEK 293) which endogenously express Kir6.1/SUR2 mRNA was stimulated by pinacidil in a dose-dependent manner, an effect that was partially abolished by glibenclamide (3 microM). In summary, Kir6.1/SUR2 channel subunits are highly expressed during early development of ureteric bud and nephron epithelia where Kir6.1/SUR2 activity regulates cell proliferation.     

Expression of MUC1, Thomsen-Friedenreich-related antigens, and cytokeratin 19 in human renal cell carcinomas and tubular clear cell lesions

The expression of MUC1, MUC2, mucin-associated Thomsen-Friedenreich-related antigens (TF, sialosyl-TF, Tn, and sialosyl-Tn), and cytokeratin 19 (CK19) was systematically investigated in situ in 58 resected human kidney tumours, surrounding tissue of normal appearance, and two normal kidneys obtained at autopsy, using monoclonal antibodies. In kidney tissues of normal appearance, TF, s-TF, MUC1 and CK19 were positive in distal tubules and collecting ducts but negative in proximal tubules. In contrast, MUC2, Tn, and s-Tn were negative throughout the normal renal tubular system. Almost all renal cell carcinomas (RCCs) showed strong immunoreactivity for MUC1, but all were negative for MUC2. Some RCCs expressed TF, Tn, s-Tn, and CK19. In addition, the immunomorphological characteristics of the majority of clear-cell RCCs and clear/granular RCCs with anti-MUC1 and anti-CK 19 closely resembled those of the collecting duct and the distal tubule rather than the proximal tubule. In the renal tissue of otherwise normal appearance adjacent to clear-cell RCCs and clear/granular RCCs, clear cells with excessive storage of glycogen were often found in the collecting duct system, but only rarely in the proximal tubules. These results suggest that the majority of clear-cell RCCs and clear/granular RCCs may originate from the collecting duct system. Received: 24 August 1999 / Accepted: 30 August 1999     

Histopathological study of human cisplatin nephropathy

The present study was conducted to obtain detailed information on the morphological changes in the human kidney as related to cisplatin therapy. The kidneys of ten autopsy cases showing impaired renal function following cisplatin therapy with hydration were examined histologically. Sporadic lesions of degeneration, necrosis, and regenerative changes were observed in the pars convoluta and pars recta of the proximal tubule, distal tubule, and collecting duct. Enlarged and pleomorphic nuclei in regenerated epithelial cells and hyperplasia of the collecting duct lining cells were considered to be specific histological findings in renal injury related to cisplatin therapy. Electron microscopic examination of a case receiving a large dose of cisplatin without signs of renal insufficiency showed an increased number of cytosomes containing electron dense granules in all tubular portions and conspicuous nuclear indentation in the thin limb of the loop of Henle and collecting duct. The platinum concentration in autopsy organs and biopsy cases was analyzed, but no correlation could be found between the concentration level of platinum in the kidney and impairment of renal function.     

Expression of NHERF-1, NHERF-2, PDGFR-alpha, and PDGFR-beta in normal human kidneys and in renal transplant rejection.

Sodium-hydrogen exchanger regulatory factor-1 and -2 (NHERF-1 and NHERF-2) are adaptor proteins that regulate renal electrolyte transport and interact with the platelet-derived growth factor receptors (PDGFR). The distribution of the NHERF proteins and PDGFR was studied in normal human kidneys and in renal transplant rejection using immunocytochemistry. In normal kidneys, NHERF-1 was detected in proximal tubules. NHERF-2 was detected in glomeruli, peritubular capillaries, and collecting duct principal cells. NHERF-2 was also weakly detected in the proximal tubule. PDGFR-beta was detected in glomeruli but not in tubules while PDGFR-alpha was detected in renal tubules and minimally in glomeruli. Acute and chronic transplant rejection was associated with increased expression of PDGFR-alpha in tubules and expression in the glomeruli. PDGFR-beta expression in the glomeruli was increased in transplant rejection and became detectable in tubules. Expression of NHERF-1 and NHERF-2 was not different in the patient groups. These results indicate that in contrast to the rat, both NHERF isoforms are detected in the human proximal tubule. In renal transplant rejection, there is increased expression of both PDGFR subtypes consistent with a role for PDGF in injury or repair.