Effect of far infrared therapy on arteriovenous fistula maturation, survival and stenosis in hemodialysis patients, a randomized, controlled clinical trial: the FAITH on fistula trial.

BACKGROUND: An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis treatment. After creation many of the AVFs will never mature or if functioning will need an intervention within 1 year due to an AVF stenosis. Studies investigating possible therapies that improves the AVF maturation and survival are scarce. Far infrared therapy (FIR) has shown promising results. In minor single centre and industry supported trials FIR has shown improved AVF maturation and survival. There is a need of a randomized multicentre controlled trial to examine the effect of FIR on the AVF maturation and survival and to explore the possible AVF protective mechanism induced by the FIR treatment. METHODS: This investigator initiated, randomized, controlled, open-labeled, multicenter clinical trial will examine the effect of FIR on AVF maturation in patients with a newly created AVF (incident) and AVF patency rate after 1 year of treatment in patients with an existing AVF (prevalent) compared to a control group. The intervention group will receive FIR to the skin above their AVF three times a week for 1 year. The control group will be observed without any treatment. The primary outcome for incident AVFs is the time from surgically creation of the AVF to successful cannulation. The primary outcome for the prevalent AVFs is the difference in number of AVFs without intervention and still functioning in the treatment and control group after 12 months. Furthermore, the acute changes in inflammatory and vasodilating factors during FIR will be explored. Arterial stiffness as a marker of long term AVF patency will also be examined. DISCUSSION: FIR is a promising new treatment modality that may potentially lead to improved AVF maturation and survival. This randomized controlled open-labelled trial will investigate the effect of FIR and its possible mechanisms. TRIAL REGISTRATION: Clinicaltrialsgov NCT04011072 (7th of July 2019).

Tooth formation and eruption - lessons learnt from cleidocranial dysplasia.

The principles of formation, renewal, and eruption of teeth are discussed. Numerous genetic aberrations may affect the formation and eruption of teeth. Cleidocranial dysplasia (CCD), caused by mutations in the runt-related transcription factor 2 (RUNX2) gene, is such a condition. The dental phenotype includes problems in both tooth formation (multiple supernumerary permanent teeth) and tooth eruption (lack of shedding of primary teeth and delayed or arrested eruption of permanent teeth). Clinical studies, animal models, and molecular biology studies have documented that RUNX2 is of paramount importance for osteoblast differentiation, for regression of the dental lamina, and for osteoclastogenesis in the dental follicle and the periodontal ligament. Jensen & Kreiborg, 25 yr ago, proposed a treatment strategy to be applied to patients with CCD, focussing on the importance of early treatment to promote spontaneous eruption of permanent teeth through extraction of primary teeth, surgical removal of supernumerary teeth, and removal of bone covering the first formed permanent teeth at the time when root formation of the permanent teeth has reached half or two-thirds of their final length. This strategy still seems valid and seems to lead to reduction in the burden of care for patients compared with the treatment protocols otherwise recommended.

The water channel AQP1 is expressed in human atherosclerotic vascular lesions and AQP1 deficiency augments angiotensin II-induced atherosclerosis in mice.

AIM: The water channel aquaporin 1 (AQP1) promotes endothelial cell migration. It was hypothesized that AQP1 promotes neovascularization and growth of atherosclerotic plaques. METHODS: AQP1 immunoreactivity and protein abundance was examined in human and murine atherosclerotic lesions and aortic aneurysms. Apolipoprotein E (ApoE) knockout (-/-) and AQP1-/-ApoE-/- mice were developed and fed Western diet (WD) for 8 and 16 weeks to accelerate the atherosclerosis process. In ApoE-/- and AQP1-/-ApoE-/- mice abdominal aortic aneurysms (AAA) were induced by angiotensin II (ANGII) infusion by osmotic minipumps for 4 weeks. RESULTS: In human atherosclerotic lesions and AAA, AQP1 immunoreactive protein was associated with intralesional small vessels. In ApoE-/- mouse aorta, APQ1 mRNA levels were increased with time on WD (n = 7-9, P < 0.003). Both in murine lesions at the aortic root and in the abdominal aortic aneurysmal wall, AQP1 immunoreactivity was associated with microvascular structures. The atherosclerotic lesion burden was enhanced significantly in ANGII-infused AQP1-/-ApoE-/- mice compared with ApoE-/- mice, but neither incidence nor progression of AAA was different. The aortic lesion burden increased with time on WD but was not different between ApoE-/- and AQP1-/-ApoE-/- mice at either 8 or 16 weeks (n = 13-15). Baseline blood pressure and ANGII-induced hypertension were not different between genotypes. CONCLUSION: AQP1 is expressed in atherosclerotic lesion neovasculature in human and mouse arteries and AQP1 deficiency augments lesion development in ANGII-promoted atherosclerosis in mice. Normal function of AQP1 affords cardiovascular protection.

TMEM16A is a Ca(2+) -activated Cl(-) channel expressed in the renal collecting duct.

AIM: In the renal collecting ducts, ATP stimulates a Ca(2+) -activated chloride current. The identity of the channel responsible for the current under physiological conditions is not known and it was hypothesized that TMEM16a is a relevant candidate in the renal collecting duct. METHODS: The cortical collecting duct cell line M-1 was used as a model of the collecting duct. The ATP induced Ca(2+) signalling was imaged in cells loaded with Ca(2+) -sensitive fluorescent probes using confocal laser-scanning fluorescence microscopy. Chloride current was determined by mounting M-1 cell layers in Ussing chamber. The expression of TMEM16a in human kidney was tested by immunohistochemistry. RESULTS: M-1 cells displayed a transient increase in intracellular Ca(2+) concentration in response to 100 nm ATP. This response was completely blocked by addition of 100 µm suramin, indicating that ATP signals through purinergic P2 receptors. Apical addition of 100 nm ATP induced a Cl(-) current, which was blocked by suramin, DPC and the cysteine-modifying compound MTSET. M-1 cells were found to express TMEM16a at the mRNA and protein level. Functionally, it was found that knock-down of TMEM16a expression in M-1 cells inhibited the ATP induced Cl(-) -current. In human and mouse kidney sections, TMEM16a protein expression was localized to the collecting duct, and TMEM16a was found to be excreted in human urinary exosomes. CONCLUSION: TMEM16a is a Ca(2+) -activated Cl(-) channel expressed in the collecting ducts.

Salt sensitivity of renin secretion, glomerular filtration rate and blood pressure in conscious Sprague-Dawley rats.

AIM: We hypothesized that in normal rats in metabolic steady state, (i) the plasma renin concentration (PRC) is log-linearly related to Na(+) intake (NaI), (ii) the concurrent changes in mean arterial pressure (MABP) and glomerular filtration rate (GFR) are negligible and (iii) the function PRC = f(NaI) is altered by ß1-adrenoceptor blockade (metoprolol) and surgical renal denervation (DNX). METHODS: In catheterized, conscious rats on low-Na(+) diet (0.004% Na(+)), NaI was increased by up to 120-fold, in four 3-day steps, by intravenous saline infusion. MABP was recorded continuously, PRC measured in arterial blood, and GFR estimated by inulin clearance. RESULTS: Steady states were achieved within 3 days. PRC [mIU L(-1)] was log-linearly related to NaI [mmol kg(-1) day(-1)]: PRC = -9.9 log (NaI) + 22. Set point (22 mIU L(-1) at NaI = 1) and slope (9.9 mIU per decade NaI) were independent of metoprolol administration and DNX. MABP and GFR were markedly salt-sensitive: MABP [mmHg] = 4.9 log (NaI) + 99 (P < 0.01), and GFR [mL min(-1)] = 1.4 log (NaI) + 8.3 (P < 0.01). MABP increased similarly (approx. 10%, P < 0.001) irrespective of pre-treatment. Metoprolol, but not DNX, reduced MABP, HR, and GFR (all P < 0.01). Salt sensitivity of GFR was not observed in DNX rats. CONCLUSION: Log-linear relations to sodium intake exist not only for PRC, but also for MABP and GFR, which per 10-fold increase in sodium intake rose by 5 mmHg and 1.4 mL min(-1) respectively. Steady-state levels of PRC appear independent of renal nerves. MABP and GFR seem markedly salt sensitive in normal rats.

Postnatal development of the renal medulla; role of the renin-angiotensin system.

Adverse events during foetal development can predispose the individual for cardiovascular disease later in life, a correlation known as foetal programming of adult hypertension. The 'programming' events have been associated with the kidneys due to the significant role in extracellular volume control and long-term blood pressure regulation. Previously, nephron endowment and functional consequences of a low nephron number have been extensively investigated without achieving a full explanation of the underlying pathophysiological mechanisms. In this review, we will focus on mechanisms of postnatal development in the renal medulla with regard to the programming effects. The renin-angiotensin system is critically involved in mammalian kidney development and impaired signalling gives rise to developmental renal lesions that have been associated with hypertension later in life. A consistent finding in both experimental animal models and in human case reports is atrophy of the renal medulla with developmental lesions to both medullary nephron segments and vascular development with concomitant functional disturbances reaching into adulthood. A review of current knowledge of the role of the renin-angiotensin system for renal medullary development will be given.

Mechanisms of renal NaCl retention in proteinuric disease.

In diseases with proteinuria, for example nephrotic syndrome and pre-eclampsia, there often are suppression of plasma renin-angiotensin-aldosterone system components, expansion of extracellular volume and avid renal sodium retention. Mechanisms of sodium retention in proteinuria are reviewed. In animal models of nephrotic syndrome, the amiloride-sensitive epithelial sodium channel ENaC is activated while more proximal renal Na(+) transporters are down-regulated. With suppressed plasma aldosterone concentration and little change in ENaC abundance in nephrotic syndrome, the alternative modality of proteolytic activation of ENaC has been explored. Proteolysis leads to putative release of an inhibitory peptide from the extracellular domain of the γ ENaC subunit. This leads to full activation of the channel. Plasminogen has been demonstrated in urine from patients with nephrotic syndrome and pre-eclampsia. Urine plasminogen correlates with urine albumin and is activated to plasmin within the urinary space by urokinase-type plasminogen activator. This agrees with aberrant filtration across an injured glomerular barrier independent of the primary disease. Pure plasmin and urine samples containing plasmin activate inward current in single murine collecting duct cells. In this study, it is shown that human lymphocytes may be used to uncover the effect of urine plasmin on amiloride- and aprotinin-sensitive inward currents. Data from hypertensive rat models show that protease inhibitors may attenuate blood pressure. Aberrant filtration of plasminogen and conversion within the urinary space to plasmin may activate γ ENaC proteolytically and contribute to inappropriate NaCl retention and oedema in acute proteinuric conditions and to hypertension in diseases with chronic microalbuminuria/proteinuria.

Apical serine protease activity is necessary for assembly of a high-resistance renal collecting duct epithelium.

AIM: We hypothesized that the serine protease prostasin is necessary for differentiation of a high-resistance renal collecting duct epithelium governed by glucocorticoid. METHODS: Postnatal rat kidney and adult human kidney was used to study the expression and localization of prostasin. The murine collecting duct cell line (M-1) was cultured in Snapwell inserts to investigate the significance of prostasin for the development of transepithelial electrical resistance (TER). RESULTS: In the cortex and medulla of rat kidney, prostasin mRNA and protein increased significantly between birth and weaning (day 21) and was detected in collecting ducts. Immunoreactive prostasin was associated with collecting ducts and loops of Henle in human kidney. In rat, adrenalectomy at day 10 had no effect on prostasin mRNA level in kidney at day 20. Cultured M-1 cells exhibited parallel increases in prostasin mRNA, protein and TER 5 days after seeding. Apical addition of the serine protease inhibitor aprotinin to M-1 cell cultures inhibited development of TER and led to aberrant localization of E-cadherin. This effect was mimicked by the protease inhibitor nafamostat. Apical addition of phospholipase C to cleave glycosylphosphatidylinositol (GPI) anchors released prostasin to the medium and attenuated development of TER with time of culture. Disruption of lipid rafts by methyl-ß-cyclodextrin attenuated development of TER in M-1 cells. Omission of dexamethasone impaired development of TER in M-1 cells, while prostasin protein abundance and E-cadherin distribution did not change. CONCLUSION: Apical, GPI-anchored, lipid raft-associated serine protease activity, compatible with prostasin, is necessary for the development of a high-resistance collecting duct epithelium.

Uridine adenosine tetraphosphate affects contractility of mouse aorta and decreases blood pressure in conscious rats and mice.

AIM: in the anaesthetized rat, uridine adenosine tetraphosphate (Up(4) A) is a circulating, endothelium-derived vasoconstrictor presumably operating as such in un-anaesthetized animals. The present study investigated the in vivo effects of Up(4) A in conscious mice and rats, and its direct vascular effects in the mouse aorta in vitro. METHODS: in vivo, Up(4) A was given as step-up infusion at rates of 8-512 nmol min(-1) kg(-1) for 30 min periods in chronically catheterized rodents. In vitro, the effect of Up(4) A on rings of mouse aortae mounted in a myograph was tested. RESULTS: high doses of Up(4) A (mice: 512 nmol min(-1) kg(-1) ; rats: 128 nmol min(-1) kg(-1) ) caused hypotension (99 (+/-)4 to 64 7(+/-) mmHg and 114 (+/-) 3 to 108 (+/-) 3 mmHg, respectively, both P < 0.01). In rats, Up(4) A significantly decreased sodium excretion by >75% and potassium excretion by approximately 60% without significant changes in urine flow. Exposure of phenylephrine-contracted rings to increasing concentrations of Up(4) A elicited contraction at 10(-7) and 10(-6) molL(-1) (18 ± 2% and 76 (+/-) 16% respectively); unexpectedly, 10(-5) molL(-1) caused a biphasic response with a contraction (19 6(+/-)2%) followed by a relaxation (-46 (+/-) 6%). No relaxation was observed when the concentration was increased further. Bolus exposure to 10(-5) molL(-1) of Up(4) A caused contraction (+80 (+/-) 2%). Added successively to untreated vessels, increasing concentrations of Up(4) A (10(-7) -10(-5) molL(-1) ) induced a biphasic response of contraction followed by relaxation. CONCLUSION: up(4) A has direct biphasic effects on vascular smooth muscle of the mouse aorta but vasoconstriction dominates at low concentrations. In conscious rodents, step-up infusions of Up(4) A elicit hypotension and electrolyte retention.

Localization and functional characterization of the human NKCC2 isoforms.

AIM: Salt reabsorption across the apical membrane of cells in the thick ascending limb (TAL) of Henle is primarily mediated by the bumetanide-sensitive Na(+)/K(+)/2Cl(-) cotransporter NKCC2. Three full-length splice variants of NKCC2 (NKCC2B, NKCC2A and NKCC2F) have been described. The NKCC2 isoforms have specific localizations and transport characteristics, as assessed for rabbit, rat and mouse. In the present study, we aimed to address the localization and transport characteristics of the human NKCC2 isoforms. METHODS: RT-PCR, in situ hybridization and uptake studies in Xenopus oocytes were performed to characterize human NKCC2 isoforms. RESULTS: All three classical NKCC2 isoforms were detected in the human kidney; in addition, we found splice variants with tandem duplicates of the variable exon 4. Contrary to rodents, in which NKCC2F is the most abundant NKCC2 isoform, NKCC2A was the dominant isoform in humans; similarly, isoform-specific in situ hybridization showed high expression levels of human NKCC2A along the TAL. Compared to NKCC2B and NKCC2F, human NKCC2A had the lowest Cl(-) affinity as determined by (86)Rb(+) uptake studies in oocytes. All NKCC2 isoforms were more efficiently inhibited by bumetanide than by furosemide. A sequence analysis of the amino acids encoded by exon 4 variants revealed high similarities between human and rodent NKCC2 isoforms, suggesting that differences in ion transport characteristics between species may be related to sequence variations outside the highly conserved sequence encoded by exon 4. CONCLUSION: The human NKCC2 is an example of how differential splicing forms the basis for a diversification of transporter protein function.

Intercellular calcium signaling and nitric oxide feedback during constriction of rabbit renal afferent arterioles.

Vasoconstriction and increase in the intracellular calcium concentration ([Ca(2+)](i)) of vascular smooth muscle cells may cause an increase of endothelial cell [Ca(2+)](i), which, in turn, augments nitric oxide (NO) production and inhibits smooth muscle cell contraction. This hypothesis was tested in microperfused rabbit renal afferent arterioles, using fluorescence imaging microscopy with the calcium-sensitive dye fura-2 and the NO-sensitive dye 4-amino-5-methylamino-2',7'-difluorescein. Both dyes were loaded into smooth muscle and endothelium. Depolarization with 100 mmol/l KCl led to a transient vasoconstriction which was converted into a sustained response by N-nitro-l-arginine methyl ester (l-NAME). Depolarization increased smooth muscle cell [Ca(2+)](i) from 162 +/- 15 nmol/l to a peak of 555 +/- 70 nmol/l (n = 7), and this response was inhibited by 80% by the l-type calcium channel blocker calciseptine. After a delay of 10 s, [Ca(2+)](i) increased in endothelial cells immediately adjacent to reactive smooth muscle cells, and this calcium wave spread in a nonregenerative fashion laterally into the endothelial cell layer with a velocity of 1.2 microm/s. Depolarization with 100 mmol/l KCl led to a significant increase in NO production ([NO](i)) which was inhibited by l-NAME (n = 5). Acetylcholine caused a rapid increase in endothelial [Ca(2+)](i), which did not transfer to the smooth muscle cells. l-NAME treatment did not affect changes in smooth muscle [Ca(2+)](i) after depolarization, but it did increase the calcium sensitivity of the contractile apparatus. We conclude that depolarization increases smooth muscle [Ca(2+)](i) which is transferred to the endothelial cells and stimulates NO production which curtails vasoconstriction by reducing the calcium sensitivity of the contractile apparatus.

Cyclooxygenase type 2 is increased in obstructed rat and human ureter and contributes to pelvic pressure increase after obstruction.

Prostanoids exert physiological effects on ureteral contractility that may lead to pressure changes and pain during obstruction. In the present study, we examined whether (1) obstruction changes the expression of the two cyclooxygenase (COX) isoforms, COX-1 and COX-2 in human and rat ureters and (2) administration of a selective COX-2 inhibitor influences the pelvic pressure change after experimental ureteral obstruction. Rats were subjected to bilateral ureter obstruction. Ureters were removed and dissected into a proximal dilated and distal non-dilated segment. RNA and protein were extracted and analyzed for cyclooxygenase expression by quantitative polymerase chain reaction and Western blotting. Human ureter samples were obtained from patients undergoing radical nephrectomy. Rat and human ureteral samples were processed for immunohistochemistry. COX-1, but not COX-2 mRNA, was readily detected in the normal rat ureter. COX-2 mRNA and protein expression was increased in the proximal dilated ureter compared to distal non-dilated ureter. This increased COX-2 expression was associated with increased urinary prostaglandin E2 (PGE2) excretion after release of obstruction. Immunohistochemistry showed increased COX-2 labeling in surface epithelium and smooth muscle layers in both rat and human obstructed ureters compared to control ureters. Furthermore, contractile PGE2-EP1 and thromboxane TP receptors were expressed in ureteral smooth muscle. Systemic treatment with the COX-2 selective inhibitor parecoxib (5 mg/kg/day) attenuated the pelvic pressure increase during obstruction. In summary, COX-2 expression is significantly increased in the ureteral wall in response to obstruction in the rat and human ureter and COX-2 activity contributes to increased pelvic pressure after obstruction.

Reduced activity of 11beta-hydroxysteroid dehydrogenase type 2 is not responsible for sodium retention in nephrotic rats.

AIM: In mineralocorticoid target cells 11-beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) converts glucocorticoids into non-active metabolites thereby protecting the mineralocorticoid receptor (MR) from stimulation by glucocorticoids. In nephrotic syndrome, a decreased activity of 11betaHSD2 has been suggested to allow glucocorticoids to stimulate MR, thereby contributing to sodium retention. We tested this hypothesis in the puromycin aminonucleoside model of nephrotic syndrome in rats. METHODS: Complete sodium and potassium intakes and excretions (faeces and urine) were measured in rats in metabolic cages. RNase protection assay of mRNA and Western blotting of protein were used to estimate renocortical expression of 11betaHSD2 and of the MR downstream effector serum and glucocorticoid induced kinase (SGK). In an intervention series, dexamethasone was given [10 microg (100 g bw)(-1)] to suppress endogenous glucocorticoids in the proteinuric stage during active sodium retention. RESULTS: Nephrotic rats developed proteinuria, positive sodium balance, decreased plasma aldosterone concentration, and decreased urinary Na(+)/K(+) ratio. 11betaHSD2 mRNA expression was down-regulated but protein expression was unchanged. SGK mRNA and phosphorylated SGK protein were up-regulated while total SGK protein expression was unchanged. Dexamethasone treatment, which suppressed plasma corticosterone concentration, did not correct sodium balance or fluid retention in nephrotic rats. CONCLUSION: Our results do not support the hypothesis that stimulation of the MR by endogenous glucocorticoids induces sodium and fluid retention in experimental nephrotic syndrome in rats.

Adrenomedullin expression during hypoxia in fetal sheep.

AIM: We asked how adrenomedullin (AM), a vasodilator peptide, was distributed in fetal sheep organs and whether expression of AM would be upregulated in response to moderate acute fetal hypoxia in vivo. METHODS: In four sheep at day 126-130 of gestation, nitrogen was added to the inspired air by tracheal infusion to reduce fetal arterial oxygen content for a period of 4 h. Control fetuses were from four ewes given a tracheal infusion of room air. Fetal and maternal blood samples were taken prior to and during hypoxia/sham hypoxia. Fetal tissue samples were frozen for RNA analysis and fixed for immunohistochemistry. RESULTS: In hypoxic fetuses, arterial oxygen content was significantly reduced to 50% compared with sham fetuses with no change in arterial pH in either group. Plasma ACTH levels rose significantly at 2 and 4 h in hypoxic fetuses only. Initial plasma concentrations of AM in control and hypoxic fetuses were 457 +/- 20 and 430 +/- 35 pg mL(-1) and did not change during the experiment. The relative abundance of AM mRNA was placental cotyledons >> lung > cerebral cortex approximately equal to renal cortex > left ventricle approximately equal to right ventricle > adrenal gland > renal medulla > aorta approximately equal to liver. Immunohistochemical staining for AM confirmed distinct labelling in organs with significant expression. AM mRNA level increased significantly in cerebral cortex of hypoxic fetuses. CONCLUSION: Our results show expression of AM in placenta and in several fetal organs in late gestation sheep. AM may participate in the cerebral vasodilatation that is an integral part of the fetal response to hypoxia.

Membrane potential and cation channels in rat juxtaglomerular cells.

The relationship between membrane potential and cation channels in juxtaglomerular (JG) cells is not well understood. Here we review electrophysiological and molecular studies of JG cells demonstrating the presence of large voltage-sensitive, calcium-activated potassium channels (BK(Ca)) of the ZERO splice variant, which is also activated by cAMP. These channels explain the hyperpolarization, which has been observed after stimulation of renin release with cAMP. In addition, there is now evidence that JG cells express functional L-type voltage-dependent calcium channels (Ca(v) 1.2), which in situations with strong depolarization lead to calcium influx and inhibition of renin release. In most in vivo situations the membrane potential is probably protected against depolarization by the BK(Ca) channels.

Rapid non-genomic effects of aldosterone on rodent vascular function.

The main role of aldosterone is to maintain body sodium homeostasis by promoting salt reabsorption in the collecting ducts of the kidney. In the cardiovascular system, aldosterone may be harmful in a number of disease states by inducing fibrosis and vascular dysfunction. The present review describes novel results from several laboratories, which show that aldosterone also has beneficial effects in the cardiovascular system by stimulating the production of nitric oxide (NO) from the endothelium. The effect of aldosterone is seen within minutes, and is not inhibited by blockers of gene transcription, thus pointing to a non-genomic mechanism. Furthermore, this potentially beneficial effect is observed at low physiological concentrations of aldosterone (0.1-10 pm). The effect is mediated by the classical mineralocorticoid receptor, and it involves heat shock protein 90, phosphatidylinositol (PI)-3 kinase, protein kinase B, endothelial nitric oxide synthase, and liberation of NO. It is proposed that in healthy individuals with a functioning NO system, the detrimental effects of aldosterone on cardiovascular function are balanced by activation of the potentially beneficial effect of NO. However, in situations with endothelial dysfunction, such as congestive heart failure and hypertension, the negative effects of aldosterone are unopposed and inhibition of aldosterone is warranted.

The renin-angiotensin system in kidney development: role of COX-2 and adrenal steroids.

Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data on the developmental changes of RAAS and COX-2 and the pathways by which they are activated; their possible interplay and the mechanisms by which they affect kidney development. Intrarenal and circulating renin and angiotensin II (ANG II) are stimulated at birth in most mammals. In rats, renin and ANG II stay significantly elevated in the suckling period while aldosterone stabilizes at an adult level. COX-2 is stimulated in thick ascending limb of Henle's loop in the suckling period at a time when urine concentrating ability is not developed. Data suggest that this induction is mediated by combined low plasma glucocorticoid concentration and by a low NaCl intake. Studies with selective inhibitors of COX-2 and COX-2 null mice show that COX-2 activity stimulates renin secretion from JG-cells during postnatal kidney development and that lack of COX-2 activity leads to pathological change in cortical architecture and eventually to renal failure. In the postnatal period, ANG II initiates and maintains pelvic and ureteric contractions necessary for urine flow. Lack of ANG II in the neonatal period is thought to cause injury by a chronic increase of renal pelvic pressure. Aldosterone is crucial for survival and growth in the neonatal period through its effects on sodium reabsorption and the intrarenal sensitivity to aldosterone is increased in the postnatal period. Final maturation of the kidney occurs through an intimate interplay between a low dietary sodium intake and a non-responsive HPA-axis which stimulates cortical COX-2 activity. COX-2 supports increased activity of the RAAS and may contribute to a low concentrating ability.