Chronic renal failure: pathophysiology.
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Animals↗
Biomedical subjects
H R Jacobson
Publications and source records attributed to H R Jacobson.
Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus.
BACKGROUND: Restriction of dietary protein may slow the progression of renal failure in diverse renal diseases, but the extent to which such a diet is beneficial in patients with diabetic nephropathy is uncertain. METHODS: We studied the effect of reduced intake of protein and phosphorus on the progression of renal disease in 35 patients with insulin-dependent (Type I) diabetes mellitus and clinically evident nephropathy. The low-protein, low-phosphorus diet contained 0.6 g of protein per kilogram of ideal body weight per day, 500 to 1000 mg of phosphorus, and 2000 mg of sodium. The control diet consisted of the patient's prestudy diet with the stipulation that it contain 2000 mg of sodium and at least 1 g of protein per kilogram per day and 1000 mg of phosphorus. Renal function was assessed by measurement of iothalamate and creatinine clearances at intervals of 3 to 6 months, and the patients were followed for a minimum of 12 months (mean, 34.7). The declines in mean glomerular filtration rates were compared between groups by linear-regression analysis of the glomerular filtration rate as a function of time. RESULTS: The patients who followed the study diet for a mean of 37.1 months had declines in iothalamate clearance of 0.0043 ml per second per month and in creatinine clearance of 0.0055 ml per second per month. The comparable values in the control group were 0.0168 and 0.0135, respectively (P less than 0.05). Blood pressure was well controlled, and the degree of glycemic control was comparable in both groups. CONCLUSION: Dietary restriction of protein and phosphorus can retard the progression of renal failure in patients with Type I diabetes mellitus who have nephropathy. We believe that wider use of this treatment is indicated.
Adult↗
Triple signal transduction model for the mechanism of PGE2 actions in rabbit cortical collecting duct.
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Animals↗
Functional characterization of alpha- and beta-intercalated cell types in rabbit cortical collecting duct.
Single-cell electrical measurements and spectrophotometric determinations of intracellular pH were used to determine unique features of alpha- and beta-intercalated cells (alpha-IC, beta-IC) in in vitro perfused rabbit cortical collecting ducts (CCD). pHi rose in alpha-IC and fell in beta-IC after bath Cl- removal. Luminal Cl- removal did not change pHi of alpha-IC, but pHi of beta-IC rose by 0.36 +/- 0.01 pH units. Cl- concentration-dependent recovery of beta-IC pHi revealed a Cl- Km of 18.7 mM for the luminal Cl(-) -HCO3- exchanger. Measurements of basolateral membrane voltage (Vbl) also showed two IC cell types. Removal of luminal Cl- did not change Vbl in alpha-IC, whereas Vbl hyperpolarized by a mean of 73.2 +/- 3.5 mV in beta-IC. Reducing bath Cl- depolarized both alpha- and beta-IC Vbl. In alpha-IC a large repolarization of 39.8 +/- 5.2 mV followed acute depolarization after bath Cl- removal. Reducing bath HCO3- (constant CO2) had little effect on beta-IC Vbl, whereas alpha-IC Vbl depolarized by 5.2 +/- 0.7 mV. Reducing luminal HCO3- in the absence of luminal Cl- produced a 17.6 +/- 1.8 mV depolarization in beta-IC. This change was independent of luminal Na+ and was not blocked by luminal 10(-4) M 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). In beta-IC, Vbl was not altered by either bath or lumen DIDS in the presence of luminal Cl-. However, when luminal Cl- was removed, luminal DIDS reversibly depolarized Vbl by 9.6 +/- 2.9 mV.(ABSTRACT TRUNCATED AT 250 WORDS)
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Glomerular stereospecific synthesis and hemodynamic actions of 8,9-epoxyeicosatrienoic acid in rat kidney.
Renal glomerular and cortical metabolism of endogenous arachidonic acid by cytochrome P-450 epoxygenase yields 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EET). Using gas chromatography-mass spectrometry, we measured the synthesis of 8,9-EET from an endogenous pool of arachidonic acid in normal rat kidney. The (8S,9R) isomer was favored over the (8R,9S) isomer in a ratio (%) of 59 to 41 in isolated glomeruli and 68 to 32 in cortex tissue. (8S,9R)- but not (8R,9S)-EET elicited dose-dependent vasoconstriction on intrarenal administration in the euvolemic Munich-Wistar rat. Micropuncture measurements of glomerular dynamics revealed that (8S,9R)-EET increased afferent arteriolar resistance (RA) leading to reductions in single-nephron plasma flow rate (QA), net transcapillary hydraulic pressure difference (delta P), and consequently single-nephron glomerular filtration rate (SNGFR). There was no significant change in the value of the glomerular capillary ultrafiltration coefficient (Kf). In the presence of a cyclooxygenase inhibitor, indomethacin, the effects of 8,9-EET were reversed. RA fell leading to increases in QA and delta P, with resultant augmentation of SNGFR. Under these conditions, a modest reduction if Kf was noted. Thus (8S,9R)-EET is a stereoselective renal vasoconstrictor, preferentially generated over its optical isomer, (8R,9S)-EET, suggesting that it is biologically relevant and implying specific structural requirements for EET receptor activation. The principal mechanism of action of 8,9-EET is preglomerular vasoconstriction. The vasoconstrictor effect of 8,9-EET is CO dependent.
8,11,14-Eicosatrienoic Acid↗
Prostaglandin E2 inhibits sodium transport in rabbit cortical collecting duct by increasing intracellular calcium.
The mechanism by which prostaglandin E2 (PGE2) inhibits sodium absorption (JNa) in the rabbit cortical collecting duct (CCD) was explored. PGE2 activates at least three signaling mechanisms in the CCD: (a) by itself PGE2 increases cAMP generation (b) PGE2 also inhibits vasopressin-stimulated cAMP accumulation, and (c) PGE2 raises intracellular calcium([Ca++]i). We tested the contribution of these signaling pathways to PGE2's effect on Na+ absorption, measuring 22Na flux (JNa) and [Ca++]i (using fura-2) in microperfused rabbit CCDs. In control studies PGE2 reduced JNa from 28.2 +/- 3.4 to 15.6 +/- 2.6 pmol.mm-1.min-1. Lowering bath calcium from 2.4 to 45 nM did not by itself alter JNa but in this setting PGE2 failed to inhibit JNa (28.6 +/- 5.4 to 38.5 +/- 4.0). In separate tubules, PGE2 raised [Ca++]i in a spike-like fashion followed by a sustained elevation. However, in 45 nM bath Ca++, PGE2 failed to produce a sustained [Ca++]i elevation. While pretreatment of CCDs with pertussis toxin blocked PGE2 inhibition of vasopressin-stimulated water permeability, it did not block the effect of PGE2 on JNa. To see if cAMP generation contributes to the effect of PGE2 on JNa, we tested the effect of exogenous cAMP, (8-chlorophenylthio(CPT)cAMP) on JNa. 0.1 mM 8-CPTcAMP reduced JNa from 35.75 +/- 2.3 to 21.6 +/- 2.2. However, the addition of PGE2 further blunted JNa to 15.9 +/- 1.3. In CCDs pretreated with indomethacin, 8-CPTcAMP did not significantly decrease JNa 33.6 +/- 2.8 vs. 28.4 +/- 2. However, superimposed PGE2 reduced JNa to 19.0 +/- 3.0. We conclude that PGE2 inhibits sodium transport predominantly by increasing intracellular calcium. This action is not mediated by a pertussis toxin-sensitive G protein. Finally, cAMP, through a cyclooxygenase-dependent mechanism, also inhibits CCD JNa and may contribute to the effects of PGE2 on JNa in the rabbit CCD.
Animals↗
Contrasting effects of various potassium salts on renal citrate excretion.
Mechanisms for the citraturic response to potassium citrate treatment were sought by assessing renal citrate clearance and acid-base status after oral administration of potassium citrate, potassium bicarbonate, and potassium chloride. After 2 weeks of treatment of eight patients with stones at a dose of 80 meq/day, urinary citrate rose significantly from 2.5 +/- 1.6 mmol/day (no drug) to 5.1 +/- 1.7 mmol/day with potassium citrate and to 4.5 +/- 1.5 mmol/day with potassium bicarbonate (P less than 0.05), but did not change significantly with potassium chloride. Citrate clearance increased from 8.0 to 27.4 mL/min with potassium citrate and 25.8 mL/min with potassium bicarbonate (P less than 0.05), but did not increase with potassium chloride. Both potassium citrate and potassium bicarbonate significantly raised urinary bicarbonate and decreased urinary ammonium, titratable acid, and net acid excretion. Potassium chloride was without effect. Effects of potassium citrate on urinary citrate, citrate clearance, and acid-base status tended to be more prominent than those of potassium bicarbonate, but these changes were not significant. Thus, the citraturic action of potassium citrate is largely accountable for by provision of an alkali load. Potassium itself had no effect in the absence of potassium deficiency.
Adult↗
The amino acid-induced alteration in renal hemodynamics is glucagon independent.
The amino acid-induced alteration in renal hemodynamics is glucagon independent. An oral protein load or i.v. administration of an amino acid solution results in an increase in glomerular filtration rate and renal plasma flow in both humans and animals. The change in renal hemodynamics has been attributed to the simultaneous induced rise in glucagon. Whether glucagon is necessary for the change in renal hemodynamics after an amino acid infusion was investigated. Two groups of dogs were used, and the experimental protocol was divided into four different periods (P1 through P4). Group I animals received an amino acid solution, and group II dogs received an equiosmolar solution of mannitol. In P1, the animals in both groups were hydrated with normal saline, whereas, in P2, the pancreatic clamp technique was used to fix the plasma glucagon levels. P2 served as a basal period in which measurements of glomerular filtration rate, renal plasma flow, and plasma glucagon were obtained. IN P3, group I animals received amino acid solution, and group II received mannitol and served as controls. In this period, an increase of 32 and 27% in glomerular filtration rate and renal plasma flow, respectively, in group I dogs was observed, whereas there were no significant changes in these parameters in group II. During this period, plasma glucagon remained still at basal level in both groups. In P4, an infusion of glucagon at a rate of 5 ng/kg/min was added to both groups. This maneuver resulted in a fourfold increase in plasma glucagon levels in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acids↗
Mechanism and regulation of proton transport in the outer medullary collecting duct.
Our understanding of transport and its regulation in the OMCDi has expanded significantly over the past 5 years. The OMCDi cells of the rabbit appear to be ideal for studying the mechanism and regulation of proton transport in a cell which is functionally similar to the alpha intercalated cell of the cortical collecting tubule. Characterization of the specific transporters at the apical and basolateral membrane allows us to explore further the mechanism whereby hormones and their second messengers regulate net transport in these cells. Simultaneous electrophysiologic measurements and determination of intracellular ion activities with fluorescent dyes, a technique we are currently employing in studies of single alpha and beta intercalated cells of the cortical collecting tubule, will be required to make progress in our study of regulation. Finally, characterization of the transporters has demonstrated that these cells are more complex than initially thought. Especially exciting is the possibility that the apical membrane proton extrusion step may be accomplished by more than one mechanism, i.e., a proton ATPase or an H(+)-K(+)-ATPase.
Animals↗
Functional effects of cytochrome P450 arachidonate metabolites in the kidney.
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Animals↗
Epoxyeicosatrienoic acids activate Na+/H+ exchange and are mitogenic in cultured rat glomerular mesangial cells.
The present study examined responses of cultured rat glomerular mesangial cells to exogenous exposure of epoxyeicosatrienoic acids (EET's), products of cytochrome P450 epoxygenase. One day after administration of 8,9- or 14,15-EET, cultured rat mesangial cells demonstrated significant increases in [3H]thymidine incorporation (10(-7) M 14,15-EET: 120 +/- 7% of control; n = 6; P less than 0.025; 10(-6) M 14,15-EET: 145 +/- 10%; n = 20; P less than 0.0005; 10(-6) M 8,9-EET: 167 +/- 31%; n = 9; P less than 0.05), which was not affected by addition of the cyclooxygenase inhibitor indomethacin. In addition to stimulation of [3H]thymidine incorporation, the epoxides stimulated mesangial cell proliferation. 14,15-EET administration induced intracellular alkalinization of 0.2-0.3 pH units, which was prevented by extracellular Na+ removal and blunted by amiloride (0.5 mM). Following intracellular acidification with NH4Cl addition and removal, greater than 85% of 3 mM 22Na uptake into mesangial cells was inhibited by 1 mM amiloride, indicating Na+/H+ exchange. Under these conditions, 14,15-EET stimulated Na+/H+ exchange by 42% and 8,9-EET stimulated Na+/H+ exchange by 59%. Neither protein kinase C depletion nor addition of the protein kinase C inhibitor, staurosporine, affected this stimulation. In [3H]myo-inositol loaded mesangial cells, no significant stimulation of phosphoinositide hydrolysis was detected in response to administration of 14,15-EET. Twenty-four hours after addition of [14C]14,15-EET, greater than 90% was preferentially esterified to cellular lipids, with predominant incorporation into phosphatidylinositol, phosphatidylethanolamine, and diacylglycerol. Thus, these results demonstrate epoxyeicosatrienoic acids stimulate Na+/H+ exchange and mitogenesis in mesangial cells. These effects do not appear to be mediated via phospholipase C activation. In addition, 14,15-EET was selectively incorporated into cellular lipids known to mediate signal transduction. These observations extend the potential biologic roles of c-P450 arachidonate metabolites to include stimulation of cell proliferation and suggest a role for these compounds in vascular and renal injury.
8,11,14-Eicosatrienoic Acid↗
Cellular mechanisms of prostaglandin E2 and vasopressin interactions in the collecting duct.
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Animals↗
Molecular mechanisms of diuretic agents.
Recent identification of the renal epithelial cell ion transporters inhibited by diuretics allows physicians to select appropriate types and doses of diuretics. The desirable and undesirable clinical consequences of these molecular mechanisms of action can also be predicted.
Absorption↗
Cytochrome P-450 arachidonate metabolites in rat kidney: characterization and hemodynamic responses.
Rat kidney cortical and medullary microsomal fractions catalyzed cytochrome P-450-linked metabolism of arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) (56 +/- 6% of total products in cortex and 10% in medulla) and 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-OHAA) (36 +/- 4% in cortex and 90% in medulla). In addition, endogenous renal generation of EETs was established by negative ion-chemical ionization mass spectrometry. The total amount of EETs present in the rat kidney was approximately 1 microgram/g wet tissue. The responses to renal arterial administration of 20-OHAA and 5,6-EET were evaluated in anesthetized euvolemic rats. 20-OHAA resulted in ipsilateral dose-dependent natriuresis without affecting systemic or renal hemodynamics or glomerular filtration rate (GFR). Equimolar doses of 5,6-EET resulted in dose-dependent renal vasoconstriction and reduced GFR but were without effect on arterial pressure or sodium excretion. During cyclooxygenase inhibition, 5,6-EET caused renal vasodilatation and augmentation of GFR. These data establish the capacity of rat kidney to metabolize AA through cytochrome P-450-dependent oxygenases and demonstrate the endogenous formation of the resulting eicosanoids. Monooxygenase and epoxygenase products exert effects on renal blood flow, GFR, and urinary sodium excretion rate, suggesting their potential relevance in the regulation of renal function.
8,11,14-Eicosatrienoic Acid↗
PGE2 inhibits AVP-induced water flow in cortical collecting ducts by protein kinase C activation.
It is well known that prostaglandin E2 (PGE2) both inhibits arginine vasopressin (AVP)-stimulated water permeability (hydraulic conductivity, Lp) in the cortical collecting duct (CCD) or, if administered alone, modestly increases Lp in the CCD. These bifunctional effects on Lp correspond to PGE2's capacity to inhibit AVP-stimulated adenylate cyclase (AC) activity, or to singularly stimulate AC activity in the collecting duct. The present studies suggest that the inhibitory effect of PGE2 on Lp may also be mediated by phosphatidylinositol (PI) hydrolysis. Using in vitro microperfused rabbit CCDs, we show that PGE2 releases Ca from intracellular stores. We also demonstrate that the inhibitory effect of PGE2 on AVP-stimulated Lp in the CCD is significantly reversed by the protein kinase C (PKC) inhibitor, staurosporine (SSP). Although PGE2 does not reduce an established water flow response to 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8-CPTcAMP), when the sequence of addition is reversed and PGE2 is added first, marked inhibition of 8-CPTcAMP-induced Lp is observed. This provides independent evidence that PGE2 can act through a mechanism separate from modulating AC activity. PGE2 inhibition of 8-CPTcAMP-induced Lp is reversed by SSP pretreatment. Finally, SSP pretreatment also markedly potentiates the capacity of PGE2 itself to increase Lp. We conclude that PGE2 releases Ca from intracellular stores and, by activating PKC, inhibits AVP-induced osmotic water flow. This suggests an important role for PI hydrolysis in mediating PGE2's effects on the CCD.
Alkaloids↗
Characterization of the proton-secreting cell of the rabbit medullary collecting duct.
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Animals↗
Glomerular responses to platelet-activating factor in the rat: role of thromboxane A2.
In view of its role as a pro-inflammatory mediator in glomerular injury, we investigated the renal cortical microcirculatory responses to the intrarenal arterial administration of platelet-activating factor (PAF) in the anesthetized euvolemic Munich-Wistar rat. Close arterial administration of PAF led to dose-dependent reductions in renal plasma flow rate (RPF), glomerular filtration rate (GFR), and filtration fraction (FF), in the absence of hypotension or hemoconcentration. Single-nephron (SN) plasma flow rate (QA), SNGFR and SNFF also fell [126 +/- 7 to 101 +/- 6 nl/min (P less than 0.005), 40.6 +/- 2.1 to 21.5 +/- 2.5 nl/min (P less than 0.005), and 0.33 +/- 0.03 to 0.21 +/- 0.03 (P less than 0.025)]. PAF increased pre- and postglomerular arteriolar resistances [2.32 +/- 0.14 to 2.73 +/- 0.19 (P less than 0.005) and 1.32 +/- 0.13 to 1.45 +/- 0.10(10)dyn.s.cm-5 (P less than 0.05)]. PAF infusion also led to a dramatic reduction in the mean value for the glomerular capillary ultrafiltration coefficient, Kf [0.058 +/- 0.012 to 0.020 +/- 0.003 nl.s-1.mmHg (P less than 0.025)]. PAF-induced changes in renal hemodynamics were abolished in the presence of the cyclooxygenase inhibitors, indomethacin and ibuprofen. When administered concomitantly with a thromboxane A2 (TxA2) receptor antagonist, PAF led to significant increases in RPF and GFR. In isolated glomeruli, PAF stimulated the biosynthesis of TxB2 in a dose-dependent manner. Thus PAF depresses rat glomerular function by inducing contraction of arteriolar and mesangial smooth muscle. These effects are likely mediated via the secondary release of TxA2.
Animals↗
Dose-dependent heterogenous actions of vasopressin in rabbit cortical collecting ducts.
In cortical collecting ducts (CCD), arginine vasopressin (AVP) has been proposed to autoinhibit its own hydrosmotic effect through stimulation of prostaglandin (PG) synthesis or binding to a receptor coupled to phosphatidylinositol (PI) hydrolysis, the so-called V1-receptor, with resultant elevation of intracellular Ca2+ concentration [( Ca2+]i) and activation of protein kinase C (PKC). Using isolated perfused rabbit CCD, we examined whether blocking the negative feedback by a PKC inhibitor, staurosporine (SSP), or a cyclooxygenase inhibitor, indomethacin (IND), enhances AVP-induced increase in hydraulic conductivity (Lp). The Lp induced by a pharmacological concentration (23 nM) of AVP was lower than that induced by 230 pM AVP. This blunted Lp response to 23 nM AVP was significantly restored by SSP or IND pretreatment. In contrast, both SSP and IND did not affect the Lp induced by 23 pM or 230 pM AVP. Fluorescence microscopy of isolated perfused CCD using fura-2 showed a spike-like increase in [Ca2+]i only by 23 nM but not by 23 or 230 pM AVP. We conclude that 1) AVP can increase [Ca2+]i, activate PKC, and stimulate PG synthesis in CCD with resultant autoregulation of its own hydrosmotic effect and 2) importantly, however, this negative feedback occurs only with pharmacologically high concentrations of AVP. Therefore it is unlikely that circulating AVP, via binding to receptors on CCD, autoregulates water transport through activating PG synthesis and/or PI breakdown.
Alkaloids↗