The urine-concentrating mechanism is one of the most fundamental functions of avian and mammalian kidneys. This particular function of the kidneys developed as a system to accumulate NaCl in birds and as a system to accumulate NaCl and urea in mammals. Based on phylogenetic evidence, the mammalian urine-concentrating mechanism may have evolved as a modification of the renal medulla's NaCl accumulating system that is observed in birds. This qualitative conversion of the urine-concentrating mechanism in the mammalian inner medulla of the kidneys may occur during the neonatal period. Human kidneys have several suboptimal features caused by the neonatal conversion of the urine-concentrating mechanism. The urine-concentrating mechanism is composed of various functional molecules, including water channels, solute transporters, and vasopressin receptors. Abnormalities in water channels aquaporin (AQP)1 and AQP2, as well as in the vasopressin receptor V2R, are known to cause nephrogenic diabetes insipidus. An analysis of the pathological mechanism involved in nephrogenic diabetes insipidus suggests that molecular chaperones may improve the intracellular trafficking of AQP2 and V2R, and, in the near future, such chaperones may become a new clinical tool for treating nephrogenic diabetes insipidus.

The extracellular calcium-sensing receptor (CaSR) located in either luminal or basolateral cell membranes of various types of renal tubules including proximal tubules, Henle's loop and collecting ducts has been thought to play a fundamental role in electrolyte metabolism. To further identify the physiological roles of the CaSR, we examined the effects of Ca 2+ and calcimimetics neomycin (Neo), gentamicin and gadolinium chloride (Gd 3+ ) on the intracellular pH (pHi) of in vitro microperfused mouse medullary thick ascending limb (mTAL) cells of Henle's loop, by loading the cells with fluorescent pH indicator 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein and measuring the ratio of fluorescence emission at 530 nm after exciting the dye at 490 and 440 nm. In a steady-state condition in Hepes-buffered solution, the pHi in the mTALs was 7.29 ± 0.04 (n = 9). A concentration of 200 μ mol/l Neo in the basolateral side decreased the pHi after 1 min by −0.13 ± 0.02 (n = 34, p < 0.0001). The other calcimimetics showed similar effects on pHi, whereas none of these calcimimetics in the lumen affected pHi. Na + removal or the inhibition of Na + and proton transport with amiloride, bumetanide, or bafilomycin did not eliminate the effect of Neo on pHi. On the other hand, Cl − removal clearly eliminated the Neo-induced pHi decrease (−0.06 ± 0.01 vs −0.00 ± 0.05 in Cl − removal, n = 4, p < 0.003). Thus, we have demonstrated for the first time that the CaSR is involved in the regulation of the pHi in the mTAL and requires Cl − to exert its effect. intracellular pH; renal medulla; chloride; amiloride; BCECF

ABSTRACT:To examine whether the functional and morphologic conversion of the neonatal ascending thin limb (ATL) of Henle's loop is related to gestational length, we evaluated the transepithelial voltages (Vts) of ATLs in perinatal mouse, hamster, rabbit, and rat kidneys. In isolated microperfused tubule preparations, Vts of neonatal ATLs were 23.8 Ϯ 1.4 in mouse, 25.7 Ϯ 2.2 in hamster, and 18.2 Ϯ 1.6 mV in rabbit. The influence of gestational length on the Vts and rat Na-K-Cl cotransporter (rNKCC2) expression pattern was also examined in perinatal rats subjected to a prolonged gestation due to either a daily s. M ammalian neonates possess a nearly mature urinediluting ability at birth (1); however, human neonates are unable to produce hypertonic urine at concentrations Ͼ400 mOsmol/kg, and rats are unable to produce hypertonic urine Ͼ600 mOsmol/kg. These observations indicate that the urineconcentrating ability is quite immature at birth (2). A number of researchers have tried to determine why the urineconcentrating ability of neonates does not reach adult levels; however, none have succeeded in explaining this phenomenon.It was first reported in the 19th century that morphologically, neonatal kidneys do not possess inner medullae (3). Subsequently, Kim et al. (4) clarified the subject by reporting that the ATL of Henle's loop of neonatal rats is also morphologically different from that of adults. They reported that the ATL in the neonatal period is very similar to the thick ascending limb (TAL) and that the tubule is replaced by the mature ATL cells after apoptosis and transformation.In an attempt to clarify the urine-concentrating mechanism in the neonatal period, we examined the renal tubular function directly in a series of experiments using in vitro tubule microperfusion technique and measured mRNAs for wellknown transporters and channels in the isolated inner medullary tubules of fetal, neonatal, and adult rat kidney (5). Our results led to a striking new concept regarding the maturating mechanism for the urine concentrating ability of mammalian neonates. We demonstrated that the renal medullary tubule organization of neonatal rats shares a marked similarity to the avian renal medulla. We postulate that the neonatal period is a phase of functional conversion of the urine concentrating mechanism from avian type to the mammalian type.In mammals, a urine-concentrating mechanism that is more dependent on urea than NaCl is the major protective response to a dry environment. In birds, both regulation of glomerular filtration and a urine-concentrating mechanism that is dependent on NaCl play important roles in fluid and electrolyte homeostasis. From the phylogenetic perspective, the urineconcentrating mechanism is unique in that it is only present in the metanephros of birds and mammals. Urine-concentrating ability develops after birth and matures during the weaning period.Changes in the renal medullary tubular transport properties of mature quail (6 -9), neonatal rats, and mature rats were compared in our previo...