Biomedical subjects

David Z Levine

Publications and source records attributed to David Z Levine.

5 recordsLinked to original sources

PubMed2006

Real-time measurement of kidney tubule fluid nitric oxide concentrations in early diabetes: disparate changes in different rodent models.

There are several reports indicating that nitric oxide (NO) plays a role in the kidney hyperfiltration seen in the early stages of diabetes mellitus (DM). Whole kidney GFR and single nephron GFR (SNGFR) have been reported to decrease after nitric oxide synthase (NOS) inhibition. To date, no direct, in vivo, quantitative NO measurements have been made within the kidney in any models of early diabetes. To assess the possible association of changes in tubular fluid nitric oxide concentrations (TF [NO]) with early diabetes, a specially modified NO electrode with a tip diameter of about 7 microm was used to measure NO in single tubules in seven rodent groups. In the Sprague-Dawley (SD) rat model, TF [NO] increased by 50% after streptozotocin (STZ) induced DM1. In the B6129G2/J mouse, control TF [NO] was more than twice the rat control value and fell by 50% after STZ treatment. In three other groups of mice-db/db (B6.Cg-m+/+Lepr(db)/J) Type II diabetic (DM2) mouse, db/m (its heterozygote), and the corresponding wild type (WT)-TF [NO] was also much higher than in the rat, and unlike the B6129G2/J STZ diabetic mouse, did not change after the onset of diabetes. Blood glucose concentrations were similar in the three diabetic groups. Accordingly, in different rodent models of diabetes, in vivo TF [NO], measured in real time, varies significantly in control animals and directionally in different models of DM1 and DM2.

Animals↗

PubMed2006

Hyperfiltration, nitric oxide, and diabetic nephropathy.

Early diabetes is often accompanied by an increased glomerular filtration rate (GFR). This hyperfiltration, which is significantly dependent upon increased nitric oxide activity, is believed to contribute to progression of diabetic nephropathy. In this article, a technique for the measurement of tubular fluid nitric oxide in vivo, in real time, is reviewed, and findings in three commonly used rodent models of diabetes are described. The mechanisms of altered tubuloglomerular feedback (TGF) in diabetes are also reviewed, with emphasis on hyperfiltration and the role of nitric oxide. New findings on the modulation of hyperfiltration in the classic type 2 diabetes db/db mouse are presented, showing suppression of the TGF mechanism and modulation of single-nephron GFR by a specific nitric oxide synthase inhibitor.

Animals↗

PubMed2005

Modulation of single-nephron GFR in the db/db mouse model of type 2 diabetes mellitus.

Hyperfiltration has been implicated in the progression toward diabetic nephropathy in type 2 diabetes mellitus (DM2). This study focuses for the first time on the in vivo modulation of single-nephron GFR (SNGFR) in the classic B6.Cg-m(+/+)Lepr(db)/J (db/db) mouse model of DM2. To obtain stable preparations, it was necessary to use a sustaining infusion of 3.3 ml.100 g body wt(-1) x h(-1), or higher. SNGFR (measured both proximally and distally) was greater in db/db vs. heterozygote (db/m) mice (P < 0.05) but not vs. the wild-type (WT) mice. The tubuloglomerular feedback (TGF) responses, determined as free-flow proximal vs. distal SNGFR differences, were significant in db/db mice (11.6 +/- 0.8 vs. 9.3 +/- 1.0 nl/min, P < 0.01), in db/m mice (8.0 +/- 0.8 vs. 7.2 +/- 0.6 nl/min, P < 0.02), and WT mice (9.9 +/- 0.6 vs. 8.9 +/- 0.7 nl/min, P < 0.05). After increasing the sustaining infusion in the db/db mice, to offset glycosuric urine losses, the SNGFR increased significantly, and the TGF response was abolished. In these volume-replete db/db mice, absolute fluid reabsorption measured both at the late proximal and distal tubular sites were significantly increased vs. db/m mice infused at 3.3 ml.100 g body wt(-1) x h(-1). After infusion of the neuronal nitric oxide synthase (nNOS) inhibitor S-methylthiocitrulline, SNGFR fell in both db/db and db/m mice. These studies show that SNGFR is elevated in this mouse model of DM2, is suppressed by nNOS inhibition, and is modulated by TGF influences that are altered by the diabetic state and responsive to changes in extracellular fluid volume.

Albuminuria↗

PubMed2004

Short-term modulation of distal tubule fluid nitric oxide in vivo by loop NaCl reabsorption.

BACKGROUND: Intrarenal nitric oxide (NO) production and signaling effects are influenced by NaCl loading. To gain further insight into NO mechanisms we determined whether rat distal tubular fluid (DTF) [NO] and collected NO may acutely change when NaCl loop delivery is altered. METHODS: An NO microelectrode was used to measure real-time DTF [NO] and DT-collected NO. With proximal flow blocked (open system), 150 mmol/L NaCl, with and without 10(-4) mol/L furosemide was perfused with measurement of loop [Cl] reabsorption. Using a closed system, DTF [NO] was also determined using several different loop perfusates. RESULTS: In the open system, perfusion with 40 nL/min of 150 mmol/L NaCl to which 10(-4) mol/L furosemide was added, DT [NO] and DT-collected NO was approximately twice that measured with perfusion of 150 mmol/L NaCl alone, while loop Cl reabsorption decreased by half. In the closed system, perfusion at 10 nL/min of 150 mmol/L NaCl + furosemide 10(-4) mol/L also induced a significant rise in DTF [NO] and collected NO. Perfusion of 10(-3) mol/L S-methyl-L-thiocitrulline (SMTC) with 150 mmol/L NaCl, induces a significant drop in DT [NO], but without a significant increase in collected NO. Furthermore, with addition of 10(-3) mol/L SMTC to the 150 mmol/L NaCl + 10(-4) furosemide perfusate, the rise in DT [NO] was prevented. Analysis of covariance showed that flow changes within, or between all groups, had no significant additional effect. CONCLUSION: In both open and closed loop perfusion systems, 10(-4) mol/L furosemide inhibition of NaCl transport stimulates net loop NO emission independent of flow; 10(-3) mol/L SMTC + 150 mmol/L NaCl reduces DT [NO], but not DT-collected NO. Short-term net NO emission from the entire loop, as collected in distal tubule fluid, increases with inhibition of loop NaCl transport.

Absorption↗

PubMed2002

Paracrine factors in tubuloglomerular feedback: adenosine, ATP, and nitric oxide.

The tubuloglomerular feedback response, the change in afferent arteriolar tone caused by a change in NaCl concentration at the macula densa, is likely initiated by the generation of a vasoactive mediator within the confines of the juxtaglomerular apparatus. Substantial progress has been made in identifying the nature of this mediator and the factors that modulate its effect on vascular tone. In support of earlier studies using P1 purinergic antagonists, the application of the knockout technique has shown that adenosine 1 receptors are absolutely required for eliciting TGF responses. The background level of angiotensin II appears to be an important cofactor determining the efficiency of A1AR-induced vasoconstriction, probably through a synergistic interaction at the level of the G protein-dependent transduction mechanism. The source of the adenosine is still unclear, but it is conceivable that adenosine is generated extracellularly from released ATP through a cascade of ecto-nucleotidases. There is also evidence that ATP may activate P2 receptors in preglomerular vessels, which may contribute to autoregulation of renal vascular resistance. Nitric oxide (NO), generated by the neuronal isoform of nitric oxide synthase in macula densa cells, reduces the constrictor effect of adenosine, but the regulation of NO release and its exact role in states of TGF-induced hyperfiltration are still unclear.

Adenosine↗