Glomerulotubular balance, dietary protein, and the renal response to glycine in diabetic rats

Slomowitz, Larry A.; Deng, Aihua; Hammes, John S.; Gabbai, Francis B.; Thomson, Scott C.

doi:10.1152/ajpregu.00610.2001

Cited by 16 publications

(12 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8 and 9) has been noted before (15) and supports a tubular hypothesis of glomerular hyperfiltration (21). Both Wistar and MWF rats adapted to chronic SGLT2 blockade by coming to rest with TGF activity near to the TGF midpoint, which is more typical of a nondiabetic animal (17).…”

Section: Discussionsupporting

confidence: 67%

Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat

Thomson

Rieg

Miracle

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

257

215

View full text Add to dashboard Cite

Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 302: R75-R83, 2012. First published September 21, 2011 doi:10.1152/ajpregu.00357.2011.-Tubuloglomerular feedback (TGF) stabilizes nephron function from minute to minute and adapts to different steady-state inputs to maintain this capability. Such adaptation inherently renders TGF less efficient at buffering long-term disturbances, but the magnitude of loss is unknown. We undertook the present study to measure the compromise between TGF and TGF adaptation in transition from acute to chronic decline in proximal reabsorption (Jprox). As a tool, we blocked proximal tubule sodium-glucose cotransport with the SGLT2 blocker dapagliflozin in hyperglycemic rats with early streptozotocin diabetes, a condition in which a large fraction of proximal fluid reabsorption owes to SGLT2. Dapagliflozin acutely reduced proximal reabsorption leading to a 70% increase in early distal chloride, a saturated TGF response, and a major reduction in single nephron glomerular filtration rate (SNGFR). Acute and chronic effects on Jprox were indistinguishable. Adaptations to 10 -12 days of dapagiflozin included increased reabsorption by Henle's loop, which caused a partial relaxation in the increased tone exerted by TGF that could be explained without desensitization of TGF. In summary, TGF contributes to long-term fluid and salt balance by mediating a persistent decline in SNGFR as the kidney adapts to a sustained decrease in Jprox.dapagliflozin; hyperfiltration AN ONGOING DISTURBANCE IN salt transport anywhere along the nephron will eventually be compensated by a combination of changes in glomerular filtration of salt, salt transport elsewhere along the nephron, and salt intake to fulfill the requirement for long-term balance. The kidney cannot obviate this requirement, but exerts some control over how it is achieved. Tubuloglomerular feedback (TGF) is one mechanism that the kidney can employ to influence how the response to an outside disturbance is compensated. TGF senses the amount of fluid and salt reaching the macula densa and evokes counterbalancing changes in single nephron glomerular filtration rate (SNGFR), thereby reducing the impact that an outside disturbance in proximal reabsorption would otherwise have on distal delivery. The usual way to measure the effectiveness of TGF is by in vivo micropuncture, which is most adapted to studying the TGF responses to events that occur on a time scale of several minutes (17). TGF responses over periods of 1-2 h have been partially characterized using carbonic anhydrase inhibitors to perturb proximal reabsorption (3). But little is known about the influence of TGF over the compensatory response to an outside disturbance lasting several days, which is the critical time frame over which the kidney regulates salt balance and blood pressure (5).The present studies were performed to...

show abstract

Section: Discussionsupporting

confidence: 67%

Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat

Thomson

Rieg

Miracle

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

257

215

View full text Add to dashboard Cite

show abstract

“…It is clear by immunostaining that NMDA-R reside in proximal tubules, where they are positioned to account for the effects of NMDA-R antagonists on basal RBF and GFR by enhancing tubular reabsorption and reducing the macula densa signal for tubuloglomerular feedback. Recent micropuncture data from our lab suggest that increased tubular reabsorption accounts for about half of the vasodilatory response to glycine infusion (17). However, these preliminary findings do not exclude the existence of NMDA-R in other kidney cells that may be revealed by future detailed study.…”

Section: Discussionmentioning

confidence: 56%

Vasodilatory N-Methyl-D-Aspartate Receptors Are Constitutively Expressed in Rat Kidney

Deng

Valdivielso

Munger

et al. 2002

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Abstract. N-methyl-D-aspartate receptor (NMDA-R) is an amino acid receptor and membrane calcium channel. NMDA-R is activated by binding of coagonists, L-glutamine and L-glycine. In the brain, calcium entry via NMDA-R activates type I nitric oxide synthase (NOS I). The kidney also contains NOS I and vasodilates in response to L-glycine. In this study, NMDA-R mRNA was demonstrated in rat kidney cortex by reverse transcriptase-PCR and cDNA sequencing. NMDA-R protein was demonstrated in kidney cortex by immunoblotting. To study the functional role of renal NMDA-R, renal hemodynamic effects of NMDA-R inhibition were assessed in rats using a blocker of the NMDA calcium channel (75 mg/kg MK-801 intraperitoneally) or an inhibitor of glycine binding to NMDA-R (30 mg/kg 5,7-dichlorokynurenic acid intraperitoneally). Renal blood flow was measured by perivascular pulse Doppler. GFR was measured by 3H-inulin clearance. Measurements were made before and during glycine infusion. Both NMDA-R antagonists caused renal vasoconstriction and attenuated the renal vasodilatory response to glycine infusion. These effects were not mediated by the renal nerves. The glycine response was not inhibited by aortic snare used to mimic the effects of NMDA-R inhibitors on basal renal blood flow. NMDA-R are expressed in kidney cortex, where they exert a tonic vasodilatory influence and may account for the vasodilatory response to glycine infusion.

show abstract

“…The relatively low concentration of Na in peri-macula densa segments evokes the transmission of inappropriate information regarding body fluid to the afferent arteriole as TG feedback signaling. Indeed, a relatively decreased salt concentration is detected in the peri-macula densa lesion [40,41]. In the recent agreement [26], luminal Na ions would inflow into macula densa cells through the B-isoform of Na-K-2Cl cotransporter and Na-H exchanger-2 in the apical membrane, stimulating ATP production and its release.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective Effect of Pioglitazone by the Prevention of Glomerular Hyperfiltration through the Possible Restoration of Altered Macula Densa Signaling in Rats with Type 2 Diabetic Nephropathy

Asakura¹,

Hasegawa²,

Takayanagi³

et al. 2013

Nephron Exp Nephrol

View full text Add to dashboard Cite

Background/Aims: Pioglitazone (PGZ), one of the thiazolidinediones, has been known to show renoprotective effects. In this study, we focused on the effect of PGZ on glomerular hyperfiltration (GHF), resultant glomerular injury and altered macula densa signaling as a cause of sustained GHF through modified tubuloglomerular feedback in rats with diabetic nephropathy. Methods: Kidneys from 24-week-old male OLETF rats and LET rats, nondiabetic controls, were used for the experiment. PGZ was administered (10 mg/kg/day, p.o.) for 2 weeks from 22 to 24 weeks of age in some of the OLETF rats (OLETF+PGZ). Results: Parameters relating GHF, kidney weight, creatinine clearance, urine albumin/creatinine ratio and glomerular surface were all increased in OLETF rats and partially restored in OLETF+PGZ rats. Expressions of desmin and TGF-β were also increased in OLETF rats and restored in OLETF+PGZ rats. The changes in TGF-β expression were confirmed to be independent of podocyte number. Finally, the immunoreactivity of neuronal nitric oxide synthase (nNOS) and cyclooxygenase 2 (COX-2) in the macula densa was assessed for the evaluation of macula densa signaling. Altered intensities of nNOS and COX-2 in OLETF rats were restored in OLETF+PGZ rats, which agreed with the gene expression analysis (nNOS: 100.2 ± 2.9% in LET, 64.2 ± 2.7% in OLETF, 87.4 ± 12.1% in OLETF+PGZ; COX-2: 100.8 ± 7.4% in LET, 249.2 ± 19.4% in OLETF, 179.9 ± 13.5% in OLETF+PGZ; n = 5) and the semiquantitative analysis of nNOS/COX-2-positive cells. Conclusion: PGZ effectively attenuated the GHF and hyperfiltration-associated glomerular injury in diabetic nephropathy. The restoration of altered macula densa signaling might be involved in the renoprotective effect of PGZ.

show abstract

Glomerulotubular balance, dietary protein, and the renal response to glycine in diabetic rats

Abstract: lar balance, dietary protein, and the renal response to glycine in diabetic rats.

Cited by 16 publications

References 20 publications

Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat

Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat

Vasodilatory N-Methyl-D-Aspartate Receptors Are Constitutively Expressed in Rat Kidney

Renoprotective Effect of Pioglitazone by the Prevention of Glomerular Hyperfiltration through the Possible Restoration of Altered Macula Densa Signaling in Rats with Type 2 Diabetic Nephropathy

Contact Info

Product

Resources

About