Renal Handling of Endogenous Lithium in Experimental Diabetes Mellitus in the Rat

Pollock, Carol; Field, Michael J.

doi:10.1111/j.1440-1681.1992.tb00439.x

Cited by 6 publications

(4 citation statements)

References 28 publications

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“…A quantitative comparison of our results with these experimental data is difficult, because GFR and plasma glucose concentrations vary widely in these studies and the micropuncture site is not precisely identified. Nonetheless, our model predictions agree qualitatively with the observed increase in the fractional reabsorption of water and sodium (diabetic vs. normal rat proximal tubule) (34,33,40,43,45).…”

Section: Metabolic Efficiency Of the Proximal Tubule In Diabetic Ratssupporting

confidence: 78%

Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition

Layton

Vallon

Edwards

2015

American Journal of Physiology-Renal Physiology

121

128

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Layton AT, Vallon V, Edwards A. Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. Am J Physiol Renal Physiol 308: F1343-F1357, 2015. First published April 8, 2015 doi:10.1152/ajprenal.00007.2015.-The objective of this study was to investigate how physiological, pharmacological, and pathological conditions that alter sodium reabsorption (T Na) in the proximal tubule affect oxygen consumption (QO 2 ) and Na ϩ transport efficiency (TNa/QO 2 ). To do so, we expanded a mathematical model of solute transport in the proximal tubule of the rat kidney. The model represents compliant S1, S2, and S3 segments and accounts for their specific apical and basolateral transporters. Sodium is reabsorbed transcellularly, via apical Na ϩ /H ϩ exchangers (NHE) and Na ϩ -glucose (SGLT) cotransporters, and paracellularly. Our results suggest that TNa/QO 2 is 80% higher in S3 than in S1-S2 segments, due to the greater contribution of the passive paracellular pathway to TNa in the former segment. Inhibition of NHE or Na-K-ATPase reduced T Na and QO 2 , as well as Na ϩ transport efficiency. SGLT2 inhibition also reduced proximal tubular T Na but increased QO 2 ; these effects were relatively more pronounced in the S3 vs. the S1-S2 segments. Diabetes increased TNa and QO 2 and reduced TNa/QO 2 , owing mostly to hyperfiltration. Since SGLT2 inhibition lowers diabetic hyperfiltration, the net effect on TNa, QO 2 , and Na ϩ transport efficiency in the proximal tubule will largely depend on the individual extent to which glomerular filtration rate is lowered. sodium transport; glucose; metabolism; diabetes DESPITE INTENSE RESEARCH, the mechanisms underlying the development of chronic kidney diseases remain incompletely understood. Renal hypoxia is thought to be a unifying pathway to chronic kidney disease (15) and, in general, is due to a mismatch between changes in renal oxygen delivery and oxygen consumption (8). Oxygen consumption in the kidney serves in large part to actively reabsorb Na ϩ . Since the proximal tubule is where more than half the filtered load of Na ϩ is reabsorbed, the goal of this study was to investigate how physiological and pathological changes in sodium transport alter O 2 consumption in the proximal tubule.Sodium reabsorption along the proximal tubule is coupled to HCO 3 Ϫ and Cl Ϫ transport: early NaHCO 3 reabsorption raises the luminal concentration of Cl Ϫ and enhances the driving force for paracellular NaCl reabsorption in the later part of the tubule. Notably, changes in O 2 consumption (Q O 2 ) do not always correlate positively with changes in Na ϩ reabsorption. Deng et al. (4) observed that blocking carbonic anhydrase with benzolamide (a proximal tubule diuretic) lowered the energy efficiency of Na ϩ reabsorption in the kidney, as it simultaneously decreased net Na ϩ reabsorption and increased overall O 2 consumption. These effects were abolished by drugs that suppress Na ϩ /H ϩ exchange or basolateral Na ϩ -HCO 3 Ϫ cotransport. Deng et al. (4) surmised that benzolamide...

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Section: Metabolic Efficiency Of the Proximal Tubule In Diabetic Ratssupporting

confidence: 78%

Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition

Layton

Vallon

Edwards

2015

American Journal of Physiology-Renal Physiology

121

128

View full text Add to dashboard Cite

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“…The central tenets of the C Li approach are that lithium is reabsorbed in the proximal tubule in direct proportion to sodium and water but is not reabsorbed in the loop of Henle and the distal nephron. Micropuncture studies in rodents indicate that the C Li approach is less accurate in some disease settings, including T1DM (Pollock & Field, ), but nevertheless it remains a valuable qualitative marker of proximal tubule function (Thomsen & Shirley, ). Our data clearly show that C Li increases with BP to a similar extent in both T1DM and non‐diabetic rats.…”

Section: Discussionmentioning

confidence: 99%

Impaired pressure natriuresis and non‐dipping blood pressure in rats with early type 1 diabetes mellitus

Culshaw

Costello

Binnie

et al. 2018

The Journal of Physiology

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Key points Type 1 diabetes mellitus increases cardiovascular risk; hypertension amplifies this risk, while pressure natriuresis regulates long‐term blood pressure.We induced type 1 diabetes in rats by streptozotocin injection and demonstrated a substantial impairment of pressure natriuresis: acute increases in blood pressure did not increase renal medullary blood flow, tubular sodium reabsorption was not downregulated, and proximal tubule sodium reabsorption, measured by lithium clearance, was unaffected.Insulin reduced blood glucose in diabetic rats, and rescued the pressure natriuresis response without influencing lithium clearance, but did not restore medullary blood flow.Radiotelemetry showed that diastolic blood pressure was increased in diabetic rats, and its diurnal variation was reduced.Increases in medullary blood flow and decreases in distal tubule sodium reabsorption that offset acute rises in BP are impaired in early type 1 diabetes, and this impairment could be a target for preventing hypertension in type 1 diabetes. AbstractType 1 diabetes mellitus (T1DM) substantially increases cardiovascular risk, and hypertension amplifies this risk. Blood pressure (BP) and body sodium homeostasis are linked. T1DM patients have increased total exchangeable sodium, correlating directly with BP. Pressure natriuresis is an important physiological regulator of BP. We hypothesised that pressure natriuresis would be impaired, and BP increased, in the early phase of T1DM. Male Sprague‐Dawley rats were injected with streptozotocin (30–45 mg/kg) or citrate vehicle. After 3 weeks, pressure natriuresis was induced by serial arterial ligation. In non‐diabetic controls, this increased fractional excretion of sodium from ∼1% to ∼25% of the filtered load (P < 0.01); in T1DM rats, the response was significantly blunted, peaking at only ∼3% (P < 0.01). Mechanistically, normal lithium clearance suggested that distal tubule sodium reabsorption was not downregulated with increased BP in T1DM rats. The pressure dependence of renal medullary perfusion, considered a key factor in the integrated response, was abolished. Insulin therapy rescued the natriuretic response in diabetic rats, restoring normal downregulation of tubular sodium reabsorption when BP was increased. However, the pressure dependence of medullary perfusion was not restored, suggesting persistent vascular dysfunction despite glycaemic control. Radiotelemetry showed that T1DM did not affect systolic BP, but mean diastolic BP was ∼5 mmHg higher than in non‐diabetic controls (P < 0.01), and normal diurnal variation was reduced. In conclusion, functional impairment of renal sodium and BP homeostasis is an early manifestation of T1DM, preceding hypertension and nephropathy. Early intervention to restore pressure natriuresis in T1DM may complement reductions in cardiovascular risk achieved with glycaemic control.

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“…Increased Na/H antiport activity was also docu mented in leukocytes from IDDM with albuminuria [22], Ng et al [22] observed that the elevated antiport activity in leukocytes is reversed by incubation with staurosporine, a protein kinase inhibitor, suggesting that protein kinase ac tivity (including PKC) in diabetic subjects may be higher; as staurosporine is not completely specific for PKC, other ki nases may also be involved. On the other hand, micropunc ture and microperfusion experiments have demonstrated that proximal tubular Na reabsorption is increased in dia betes meliitus [23,24]. It is possible that, similarly to blood cells, the renal Na /H countertransport could be activated, so causing the increment in tubular acidification and Na Values are means ± SE; n = number of measurements/'number o f tubules/number of rats.…”

Section: Discussionmentioning

confidence: 99%

Alterations of the Renal Handling of H<sup>+</sup> in Diabetic Rats

Gomes

Gil²,

Mello-Aires³

1997

Kidney Blood Press Res

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Renal acid excretion and proximal and distal nephron acidification were evaluated 20 days after induction of diabetes, in rats, by intraperitoneal injection of streptozotocin (45 mg/kg). Titratable acidity in urine was measured by microtitration and ammonium excretion (NH⁺₄) by spectrophotometry. Proximal tubular acidification was evaluated by the kinetics of reabsorption of perfused HCO^-₃ Distal nephron acidification was evaluated by measuring urine – blood pCO₂ differences under alkaline overload. The net acid excretion (titratable acidity + NH⁺₄-HCO^-₃) was higher (p < 0.001) in diabetic rats (9.82 ± 0.65 µmol/min/kg, n = 26) than in the control group (6.34 ± 0.14, n = 24). Proximal HCO^-₃ reabsorption was also higher (p < 0.001) in diabetic rats (8.38+0.11 nmol/cm²/s, n = 12) than in the control group (2.30 ± 0.10, n = 22); however, evaluation of distal nephron H⁺ secretion by urine – blood pCO² methodology was similar in both groups. We concluded that in rats with induced diabetes mellitus there is an increased rate of proximal HCO^-₃ reabsorption, possibly effected by a higher density of Na⁺/H⁺ antiporter in the luminal membrane of the proximal tubule and by an increased proton-motive force of the H⁺ secretory mechanism. The higher rates of H⁺ secretion generate lower stationary proximal luminal pH and probably maintain the blood pH within the physiological range.

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Renal Handling of Endogenous Lithium in Experimental Diabetes Mellitus in the Rat

Cited by 6 publications

References 28 publications

Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition

Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition

Impaired pressure natriuresis and non‐dipping blood pressure in rats with early type 1 diabetes mellitus

Alterations of the Renal Handling of H<sup>+</sup> in Diabetic Rats

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