UT-B1 urea transporter is expressed along the urinary and gastrointestinal tracts of the mouse.

Selective transporters account for rapid urea transport across plasma membranes of several cell types. UT-B1 urea transporter is widely distributed in rat and human tissues. Because mice exhibit high urea turnover and are the preferred species for gene engineering, we have delineated UT-B1 tissue expression in murine tissues. A cDNA was cloned from BALB/c mouse kidney, encoding a polypeptide that differed from C57BL/6 mouse UT-B1 by one residue (Val-8-Ala). UT-B1 mRNA was detected by RT-PCR in brain, kidney, bladder, testis, lung, spleen, and digestive tract (liver, stomach, jejunum, colon). Northern blotting revealed seven UT-B1 transcripts in mouse tissues. Immunoblots identified a nonglycosylated UT-B1 protein of 29 kDa in most tissues and of 36 and 32 kDa in testis and liver, respectively. UT-B1 protein of gastrointestinal tract did not undergo N-glycosylation. Immunohistochemistry and in situ hybridization localized UT-B1 in urinary tract urothelium (papillary surface, ureter, bladder, and urethra), prominently on plasma membranes and restricted to the basolateral area in umbrella cells. UT-B1 was found in endothelial cells of descending vasa recta in kidney medulla and in astrocyte processes in brain. Dehydration induced by water deprivation for 2 days caused a tissue-specific decrease in UT-B1 abundance in the urinary bladder and the ureter.

Urea transporter expression in aging kidney and brain during dehydration.

Aging is commonly associated with defective urine-concentrating ability. The present study examined how the kidney and the brain of senescent (30-mo-old) female WAG/Rij rats respond to dehydration induced by 2 days of water deprivation in terms of urea transporter (UT) regulation. In euhydrated situation, senescent rats exhibited similar vasopressin plasma level but lower urine osmolality and papillary urea concentration and markedly reduced kidney UT-A1, UT-A3, and UT-B1 abundances compared with adult (10-mo-old) rats. Senescent rats responded to dehydration similarly to adult rats by a sixfold increase in vasopressin plasma level. Their papillary urea concentration was doubled, without, however, attaining that of dehydrated adult rats. Such an enhanced papillary urea sequestration occurred with a great fall of both UT-A1 and UT-A3 abundances in the tip of inner medulla and an increased UT-A1 abundance in the base of inner medulla. UT-A2 and UT-B1 were unchanged. These data suggest that the inability of control and thirsted senescent rats to concentrate urine as much as their younger counterparts derives from lower papillary urea concentration. In aging brain, UT-B1 abundance was increased twofold together with a fourfold increase in aquaporin-4 abundance. Dehydration did not alter the abundance of these transporters.

UT-B1 proteins in rat: tissue distribution and regulation by antidiuretic hormone in kidney.

UT-B1 is the facilitated urea transporter of red blood cells (RBCs) and endothelial cells of descending vasa recta in the kidney. Immunoblotting with a polyclonal antibody against the C-ter sequence of rat UT-B1 revealed UT-B1 as both nonglycosylated (29 kDa) and N-glycosylated (47.5 and 33 kDa) proteins in RBC membranes, kidney medulla, brain, and bladder in rat. In testis, UT-B1 was expressed only as a nonglycosylated protein of 47.5 kDa. Immunocytochemistry confirmed that the location of UT-B1 is restricted to descending vasa recta. In brain, UT-B1 protein was found in astrocytes and ependymal cells. Cell bodies and perivascular end feet of astrocytes were labeled in brain cortex, whereas astrocyte cell processes were labeled in corpus callosum. Flow cytometry analysis of RBCs revealed a good cross-reactivity of the antibody with mouse and human UT-B1. UT-B1 protein expression in rat kidney medulla was downregulated greatly by long-term [deamino-Cys(1),D-Arg(8)]vasopressin infusion and moderately by furosemide treatment. This study discloses an uneven distribution of UT-B1 protein within astrocytes and the regulation of renal UT-B1 protein by antidiuretic hormone.

Food restriction prevents age-related polyuria by vasopressin-dependent recruitment of aquaporin-2.

The mechanisms underlying the prevention of age-related polyuria by chronic food restriction were investigated in female WAG/Rij rats. The decreased osmolality of renal papilla observed in senescent rats was not corrected by food restriction. A reduced urea content in the inner medulla of senescent rats, fed ad libitum or food-restricted, was suggested by the marked decrease in expression of UT-A1 and UT-B1 urea transporters. Aquaporin-2 (AQP2) downregulation in the inner medulla of senescent rats was partially prevented by food restriction. Both AQP2 and the phosphorylated form of AQP2 (p-AQP2), the presence of which was diffuse within the cytoplasm of collecting duct principal cells in normally fed senescent rats, were preferentially targeted at the apical region of the cells in food-restricted senescent animals. Plasma vasopressin (AVP) was similar in 10- and 30-mo-old rats fed ad libitum, but was doubled in food-restricted 30-mo-old rats. This study indicates that 1) kidney aging is associated with a marked decrease in AQP2, UT-A1, and UT-B1 expression in the inner medulla and a reduced papillary osmolality; and 2) the prevention of age-related polyuria by chronic food restriction occurs through an improved recruitment of AQP2 and p-AQP2 to the apical membrane in inner medulla principal cells, permitted by increased plasma AVP concentration.

Aquaporin-2 and urea transporter-A1 are up-regulated in rats with type I diabetes mellitus.

AIMS/HYPOTHESIS: Although the urine flow rate is considerably higher in diabetes mellitus, water reabsorption is greatly increased to concentrate an increased amount of solutes. Our study evaluated the expression of aquaporins and urea transporters, which are essential to the urinary concentration process. METHODS: Northern blot and immunoblot were used to quantify mRNA and proteins for aquaporin-2 (AQP2) as well as urea transporters UT-A1, UT-A2 and UT-B1, in subzones of the renal medulla of rats with streptozotocin-induced diabetes. RESULTS: In these rats, glycaemia, urine flow rate and water reabsorption were respectively fourfold, nine-fold and fourfold those of control rats. The AQP2 protein isoforms were significantly up-regulated in outer and inner medulla. In the base and tip of inner medulla, UT-A1 mRNA was significantly up-regulated (three- and 1.3-fold, respectively) as well as the 117 kD protein (ten- and threefold, respectively) whereas the 97 kD protein was not changed or decreased twofold, respectively. This suggests that, in diabetes, the inner medullary collecting duct is endowed with more UT-A1, especially in its initial part. In the case of mRNA and proteins of UT-A2, located in thin descending limbs in the inner stripe of outer medulla, they were respectively not changed and down-regulated in diabetic rats. CONCLUSION/INTERPRETATION: This study shows that in diabetes, the increased expression of AQP2 and UT-A1 in medullary collecting duct is consistent with an improved concentrating activity. In addition, the underexpression of UT-A2 and the overexpression of UT-A1 in the initial medullary collecting duct are reminiscent of the changes seen after experimental reduction of urine concentration or low protein feeding.

Massive reduction of urea transporters in remnant kidney and brain of uremic rats.

BACKGROUND: The facilitated urea transporters (UT), UT-A1, UT-A2, and UT-B1, are involved in intrarenal recycling of urea, an essential feature of the urinary concentrating mechanism, which is impaired in chronic renal failure (CRF). In this study, the expression of these UTs was examined in experimentally induced CRF. METHODS: The abundance of mRNA was measured by Northern analysis and that of corresponding proteins by Western blotting in rats one and five weeks after 5/6 nephrectomy (Nx). RESULTS: At five weeks, urine output was enhanced threefold with a concomitant decrease in urine osmolality. The marked rise in plasma urea concentration and fall in urinary urea concentration resulted in a 30-fold decrease in the urine/plasma (U/P) urea concentration ratio, while the U/P osmoles ratio fell only fourfold. A dramatic decrease in mRNA abundance for the three UTs was observed, bringing their level at five weeks to 1/10th or less of control values. Immunoblotting showed complete disappearance of the 97 and 117 kD bands of UT-A1, and considerable reduction of UT-A2 and UT-B1 in the renal medulla. Similar, but less intense, changes were observed at one-week post-Nx. In addition to the kidney, UT-B1 is also normally expressed in brain and testis. In the brain, its mRNA expression remained normal one-week post-Nx, but decreased to about 30% of normal at five-weeks post-Nx, whereas no change was seen in testis. CONCLUSIONS: (1) The decline in urinary concentrating ability seen in CRF is largely due to a major reduction of UTs involved in the process of urea concentration in the urine, while factors enabling the concentration of other solutes are less intensely affected. (2) The marked reduction of brain UT expression in CRF may be responsible for brain edema of dialysis disequilibrium syndrome observed in some patients after fast dialysis.

Renal urea transporters. Direct and indirect regulation by vasopressin.

Urea is the most abundant urinary solute and is excreted in urine at a much higher concentration than in other body fluids. Urea concentration is achieved in the kidney through complex urea movements between blood vessels and renal tubules, which involve facilitated urea transport. Three major urea transporters expressed in the kidney have been cloned, UT-A1, UT-A2 and UT-B1, the first two derived from the same gene by differential transcription. These membrane proteins enable facilitated diffusion of urea through specific parts of the nephron (UT-A) and through renal vasculature (UT-B) in the medulla. UT-A1 is localised in the terminal part of the inner medullary collecting ducts and accounts for the vasopressin-dependent increase in urea permeability of this segment. UT-A2 is found in the descending thin limbs of Henle's loops. UT-B1 is expressed in the endothelium of the descending vasa recta supplying blood to the renal medulla, and in red cells. All three urea transporters are primarily involved in the process of intrarenal urea recycling, which enables the establishment, and prevents the dissipation, of a high concentration of urea in the inner medulla. This is an essential feature for producing a concentrated urine and thus for water economy in mammals. Vasopressin, upon binding to V2 receptors in the inner medullary collecting ducts, increases urea permeability through activation of UT-A1 molecules, thus enabling urea to diffuse into the inner medullary interstitium. Urea then taken up in ascending vasa recta is returned to the inner medulla via UT-A2 and UT-B1 by countercurrent exchange. These latter two urea transporters are not influenced acutely by vasopressin, but UT-A2 expression is markedly increased in the descending thin limbs of the loops of Henle after sustained exposure to vasopressin or its V2 agonist dDAVP. This effect is indirect because vasopressin receptors are lacking in the descending limbs. The acute direct and delayed indirect actions of vasopressin on renal urea transporters will increase medullary urea accumulation and thus the ability of the kidney to conserve water. Atrial natriuretic peptide inhibits the vasopressin-dependent increase in urea permeability in the inner medullary collecting ducts. The interruption of urea recycling probably contributes to the natriuresis. Impairing in this way the capacity of the kidney to concentrate urea enhances its capacity to concentrate sodium in the urine.

Hyperosmotic NaCl and urea synergistically regulate the expression of the UT-A2 urea transporter in vitro and in vivo.

The UT-A2 urea transporter is involved in the recycling of urea through the kidney, a process required to maintain high osmotic gradients. Dehydration increases UT-A2 expression in vivo. The tissue distribution of UT-A2 suggested that hyperosmolarity, and not vasopressin, might mediate this effect. We have analyzed the regulation of UT-A2 expression by ambiant osmolarity both in vitro (mIMCD3 cell line) and in vivo (rat kidney medulla). The UT-A2 mRNA was found to be synergistically up-regulated by a combination of NaCl and urea. Curiously, the UT-A2 protein was undetectable in this hypertonic culture condition, or after transfection of the UT-A2 cDNA, whereas it could be detected in HEK-293 transfected cells. Treating rats with furosemide, a diuretic which decreases the kidney interstitium osmolarity without affecting vasopressin levels, led to decreased levels of the UT-A2 protein. Our results show that the UT-A2 urea transporter is regulated by hyperosmolarity both in vitro and in vivo.

Vasopressin contributes to hyperfiltration, albuminuria, and renal hypertrophy in diabetes mellitus: study in vasopressin-deficient Brattleboro rats.

Diabetic nephropathy represents a major complication of diabetes mellitus (DM), and the origin of this complication is poorly understood. Vasopressin (VP), which is elevated in type I and type II DM, has been shown to increase glomerular filtration rate in normal rats and to contribute to progression of chronic renal failure in 5/6 nephrectomized rats. The present study was thus designed to evaluate whether VP contributes to the renal disorders of DM. Renal function was compared in Brattleboro rats with diabetes insipidus (DI) lacking VP and in normal Long-Evans (LE) rats, with or without streptozotocin-induced DM. Blood and urine were collected after 2 and 4 weeks of DM, and creatinine clearance, urinary glucose and albumin excretion, and kidney weight were measured. Plasma glucose increased 3-fold in DM rats of both strains, but glucose excretion was approximately 40% lower in DI-DM than in LE-DM, suggesting less intense metabolic disorders. Creatinine clearance increased significantly in LE-DM (P < 0.01) but failed to increase in DI-DM. Urinary albumin excretion more than doubled in LE-DM but rose by only 34% in DI-DM rats (P < 0.05). Kidney hypertrophy was also less intense in DI-DM than in LE-DM (P < 0.001). These results suggest that VP plays a critical role in diabetic hyperfiltration and albuminuria induced by DM. This hormone thus seems to be an additional risk factor for diabetic nephropathy and, thus, a potential target for prevention and/or therapeutic intervention.

mRNA expression of renal urea transporters in normal and Brattleboro rats: effect of dietary protein intake.

Differences in dietary protein level induce differences in fractional excretion of urea, in arginine vasopressin (AVP) plasma level, and in urine concentrating activity (in which intervene the renal urea transporters (UT)). The abundance of mRNA for UT-A1 (of the inner medullary collecting duct, IMCD) UT-A2 (of the descending thin limb) and UT-B1 (of descending vasa recta) was determined by Northern analysis of total RNA extracted from medullary subregions of Sprague-Dawley rats fed for 1 week, a low, normal, or high protein diet. The implication of AVP was then examined by studying AVP-deprived (Brattleboro) rats. Our results show that none of these transporters is affected by the level of protein intake, except UT-A1 that is reduced in terminal IMCD by low protein diet in the absence of AVP (Brattleboro rats). These data suggest that (1) the previously reported effect of kidney medulla hypertonicity on UT-A2 and UT-B1 mRNA expression is somehow obliterated by protein intake deficiency or excess, and (2) AVP influences the mRNA abundance of the UT-A1 of the terminal IMCD during protein deficiency.

Integrated function of urea transporters in the mammalian kidney.

Specific urea transporters are responsible for the rapid urea movements occurring in precise medullary structures of the mammalian kidney. Three of them, ensuring facilitated passive transports, have been cloned yet: UT2-long is responsible for the high vasopressin-dependent urea permeability of the terminal inner medullary collecting ducts; UT2-short is located along a short portion of the thin descending limbs of Henle's loops; UT11 is expressed along the descending vasa recta. These three transporters are involved in the accumulation of urea in the medulla, participating to the corticopapillary osmotic gradient required for urine concentration in the presence of antidiuretic hormone. UT2-long enables diffusion of urea in the inner medulla, and UT2-short and UT11 enable the recycling of this urea by counter-exchange. These transporters could also be involved in nitrogen balance by modulation of their expression according to the need for urea excretion (protein-rich diet), or for nitrogen conservation (protein-poor diet). Several other urea transporters, including active transporters responsible for urea secretion or reabsorption, remain to be cloned and characterized.

Renal tubular and vascular urea transporters: influence of antidiuretic hormone on messenger RNA expression in Brattleboro rats.

In the kidney, facilitated urea transport in precise vascular and tubular structures is mainly involved in water conservation. Three urea transporters have been cloned: UT2-long expressed in terminal inner medullary collecting duct (IMCD), UT2-short expressed in thin descending limb, and UT11 in descending vasa recta. The effect of arginine vasopressin (AVP) administration on mRNA expression of these three transporters was examined in Brattleboro rats with diabetes insipidus. V2 effects were discriminated from combined V1 + V2 effects by comparing treatments with 1-deamino-8-D-AVP (dDAVP) (selective V2 agonism) and AVP (V1 and V2 agonism). Acute and chronic treatments were studied. Abundance of specific mRNA was assessed by quantitative Northern blot analysis of RNA extracted from two regions of inner stripe of outer medulla and from two regions of inner medulla (IM). The results show that mRNA of these urea transporters are differently regulated by AVP. (1) Long-term treatment with either AVP or dDAVP does not alter UT2-long mRNA in tip IM (terminal IMCD) except for a transient initial decrease. (2) Unlike AVP, dDAVP induces the appearance of significant expression of UT2-long mRNA in base IM (initial IMCD), indicating a major V2 effect. (3) UT2-short mRNA in deep inner stripe of outer medulla and base IM (thin descending limb of short and long loops, respectively) is progressively upregulated with duration of AVP or dDAVP treatment. (4) The much higher changes in UT2-long and UT2-short induced by dDAVP compared with AVP suggest that they are dependent mainly on V2 agonism, and likely attenuated by V1 agonism. (5) UT11 mRNA expression in tip IM is equally depressed by AVP and dDAVP, indicating that this vascular transporter is also influenced by AVP and/or urine-concentrating activity, via an indirect mechanism that remains to be determined.

Messenger RNA for enzymes of ornithine and polyamine metabolism are selectively underexpressed in kidney of 5/6 nephrectomized rats.

Altered nitrogen metabolism is a feature of chronic renal failure (CRF). The present study examined changes in renal expression of mRNA for enzymes involved in ornithine and polyamine metabolism, i.e. ornithine aminotransferase (OAT), ornithine decarboxylase (ODC), and S-adenosylmethionine synthetase (S-ADMase), during the early phase of renal insufficiency in rats after 5/6 nephrectomy (Nx). Involvement of androgens, the most potent stimulators of renal ODC, in these changes, was also evaluated inasmuch as testoseronemia is known to be significantly decreased in male uremic subjects. The abundance of mRNA was evaluated by quantitative Northern analysis of total RNA extracted from the remnant kidney of male or female Nx rats. The level mRNA for ODC was depressed by 76, 83, and 79%, that for OAT by 60, 76 and 63%, and that for S-ADMase by 37, 58 and 30%, at, respectively, 2, 7 and 35 days after Nx, in both male and female rats. ODC but not OAT enzyme activity was decreased. The expression of glyceraldehyde-3-phosphate dehydrogenase was only slightly lowered and that of c-myc was unaltered. Renal polyamine content of the remnant kidney was unchanged. It is concluded that in CRF: (1) intrarenal ornithine metabolism and polyamine biosynthesis are greatly impaired; (2) decreased androgens are not involved in these changes; (3) increased ODC is not a prerequisite for kidney hypertrophy; (4) extrarenal polyamines accumulation into the remnant likely compensates for defective renal biosynthesis.

Direct and indirect cost of urea excretion.

Urea, the major end product of protein metabolism in mammals, is the most abundant solute in the urine. Urea excretion is thought to result from filtration curtailed by some passive reabsorbtion along the nephron. This reabsorption is markedly enhanced by vasopressin and slow urinary flow rate (V), the fraction of filtered urea excreted in the urine (FEurea) falling from approximately 60% at high V to only approximately 20% at low V. In concentrated urine, normal urea excretion can be maintained only if urea filtration is elevated. This can be achieved by increasing plasma urea concentration (Purea) and/or GFR. We have shown that both parameters do increase when normal rats are submitted to chronic alterations in the water intake/vasopressin axis within the normal range of physiologic regulation. This situation is very similar to that observed after alterations in protein intake. In both cases more urea needs to be filtered, either because more of it has to be excreted, or because the efficiency of its excretion is reduced. A common mechanism is proposed to explain the rise in GFR observed in the two situations. In summary, our studies demonstrate that the antidiuretic effects of vasopressin are responsible for a significant elevation of GFR. This GFR adaptation limits the rise in Purea, a favorable effect because urea is not as harmless as usually thought. However, this hyperfiltration might have deleterious consequences in diseased kidneys.

Evidence for distinct vascular and tubular urea transporters in the rat kidney.

Facilitated urea transport has been demonstrated in several mammalian tissues, including those of the collecting ducts and red blood cells. Two urea transporters have been recently cloned: UT2, expressed in rabbit inner medullary collecting ducts, and HUT11, expressed in human erythrocytes. Because of significant identity (63%) between these two transporters, and because HUT11 is also expressed in the human kidney, they could represent the same transporter with species-related differences in their-sequences. In the study presented here, two different cDNA fragments, corresponding to the rat equivalents (rUT2 and rUT11) of the two previously cloned urea transporters, were isolated by reverse transcription-polymerase chain reaction. These rat probes were used for Northern analysis of RNA extracted from rat tissues. From the following findings, the results show that rUT2 and rUT11 are two distinct urea transporters: (1) The two cDNA fragments isolated in the rat exhibit different sequences; (2) The mRNA for rUT2 is found exclusively in the kidney, with two transcripts (3.2- and 4.4-kilobase (kb)), whereas rUT11 (only one transcript, 4.2 kb) is present in the brain, spleen, kidney, and testis; (3) in the kidney, the inner stripe of the outer medulla expresses rUT11 mRNA and the short transcript of rUT2, whereas the inner medulla expresses rUT11 and the two rUT2 transcripts; (4) In hydronephrotic kidneys that have completely lost their tubular epithelium but have intact vasculature, rUT2 transcripts are no longer expressed, whereas expression of rUT11 is intensified; (5) Experimental chronic alterations in urine concentrating activity induced different changes in the expression of rUT2 and rUT11.

Effect of chronic renal failure on the abundance of mRNA for enzymes of intermediary metabolism in kidney and liver.

In chronic renal failure (CRF), renal ammoniagenesis and handling of ornithine cycle intermediates (ornithine, citrulline, and arginine) are disturbed. The present study examined the molecular mechanisms of these disturbances in kidney and liver of rats with moderate CRF induced by 5/6 nephrectomy. The steady state level of mRNA for phosphoenolpyruvate carboxykinase (PEPCK) and argininosuccinate synthetase (ASS) in both kidney and liver were unaffected by CRF. On the other hand, that for phosphate-dependent glutaminase (PDG) was increased while that for ornithine decarboxylase (ODC) was decreased in the diseased kidney. Combined with previously reported enzymatic activities, our findings suggest that, in CRF, gene expression is responsible for enzymatic changes of PDG and ODC, not of PEPCK and ASS. Underexpression of ODC, resulting in impaired renal polyamine synthesis, may contribute to progression of CRF. Finally, the significant increase in renal mRNA expression of beta-actin precludes the use of this molecule as a reference in CRF.

Is the process of urinary urea concentration responsible for a high glomerular filtration rate?

For subjects on a normal diet, urea is the major urinary solute and is markedly concentrated in the urine compared with in the plasma. Because urea is not known to undergo active secretion, its excretion rests on filtration lessened to a variable extent by tubular reabsorption. It is well established that the efficiency of urea excretion drops with increasing urinary concentration and decreasing urinary flow rate (from approximately 60% of filtered load, above 2 mL/min, to approximately 20% below 0.5 mL/min) because the prolonged transit time in the distal nephron favors passive urea reabsorption. Thus, a higher urinary concentration is achieved at the expense of a reduced efficiency of urea excretion. Recent experimental observations suggest that GFR could actually increase in parallel with the urinary concentrating activity, thus ensuring a normal urea excretion in the face of a high, concentration-dependent urea reabsorption, with only a moderate increase in plasma urea. A possible mechanism is proposed that could explain how the vasopressin-induced intrarenal recycling of urea (which contributes to improvement in urinary concentration), but not an exogenous urea administration, could indirectly depress the tubuloglomerular feedback and hence increase GFR. An increased concentration of an osmotically active solute in the thick ascending limb of Henle's loop (such as urea and, in some cases, glucose) could enable a lower NaCl concentration to be achieved at the macula densa by reducing the osmotically driven water leakage in this nephron segment. This mechanism could explain the hyperfiltration seen in various pathophysiologic situations such as chronic vasopressin infusion, high protein intake, severe burns, and diabetes mellitus. Whatever the mechanism, if the need to excrete relatively high amounts of urea in a concentrated urine leads to a sustained elevation of GFR, the price to pay for this water economy is higher than generally assumed. It is not limited to the energy spent in the sodium reabsorption providing the "single effect" for the urinary concentrating process. It also includes the consequences on the glomerular filter of sustained high pressure and flow and the energy spent in reabsorbing the extra load of solutes filtered. In chronic renal failure, the ability to form hypertonic urine declines but is nevertheless well preserved with respect to declining GFR, thus imposing on remnant nephrons an additional permanent stimulus for hyperfiltration.(ABSTRACT TRUNCATED AT 400 WORDS)

Adaptation of the medullary thick ascending limb to dietary protein intake.

Since the renal growth response to a high-protein diet is characterized by prominent hypertrophy of the medullary thick ascending limb of Henle's loop (MTAL), the functional and metabolic adaptations of this nephron segment to dietary protein were investigated. MTAL suspensions were obtained from rats fed equal amounts of isocaloric food containing either 10% (LP) or 32% (HP) casein for 4-6 weeks. The results show that intact MTAL of HP rats exhibit a blunted respiration rate, sodium pump activity, hormone-sensitive cAMP production and leucine oxidation rate in comparison with those of LP rats. On the other hand, adenylate cyclase and leucine transaminase activities, measured on permeabilized or homogenized MTAL, are enhanced by a HP diet. We conclude that the MTAL adapts to high dietary protein by increasing its maximal enzyme activities, but certain factors, present in intact cells, limit transport and metabolism in HP- more than in LP-fed rats. This reduced function per unit MTAL protein in HP rats is more than compensated for by hypertrophy of the MTAL tissue mass.

Vasopressin-dependent kidney hypertrophy: role of urinary concentration in protein-induced hypertrophy and in the progression of chronic renal failure.

Recent experiments have shown that the kidney adapts to chronic variations in urine concentration. Glomerular filtration rate (GFR), kidney weight relative to body weight, thickness of inner stripe of the outer medulla, volume of epithelium in early thick ascending limb, and internephron heterogeneity are all decreased by chronic water diuresis and increased by chronic stimulation of urine concentration. It was further shown that the intrarenal pattern of hypertrophy observed after high protein (HP) intake, but not that observed after compensatory hypertrophy or normal growth with age, is exactly similar to that observed after chronic stimulation of urine concentration. Since solute-free water reabsorption (TcH2O) is markedly enhanced by HP diet, this suggests that the increases in GFR and renal mass observed after HP intake are, at least in part, an adaptive response of the kidney to increased urinary concentrating activity. The beneficial effects are induced by protein restriction in chronic renal failure (CRF) could thus be due, in part, to the reduction of this concentrating activity. This hypothesis was confirmed by an experiment performed in rats with experimental chronic renal failure (CRF) in which a chronic increase in water intake, reducing urine osmolality and TcH2O, without any change in food composition or consumption, reduced proteinuria, systemic hypertension, kidney hypertrophy, incidence of glomerulosclerosis, and mortality.