Renal Tubular Handling of Glucose and Fructose in Health and Disease

Vallon, Volker; Nakagawa, Takahiko

doi:10.1002/cphy.c210030

Cited by 15 publications

(11 citation statements)

References 418 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As such, these concentrations are expected in the early nephron lumen of both humans and rodents. Recent calculations have estimated that, on average, healthy human kidneys filter 4 to 25 g of fructose per day, an amount corresponding to ∼ 8% of the filtered glucose (51). Additionally, fructose produced by the polyol pathway in the kidney medulla could constitute a source of interstitial fructose in the kidney.…”

Section: Discussionmentioning

confidence: 99%

Profiling cellular heterogeneity and fructose transporter expression in the rat nephron by integrating single-cell and microdissected tubule segment transcriptomes

Zhang,

Jadhav,

Kramer

et al. 2023

Preprint

View full text Add to dashboard Cite

Single-cell RNA sequencing (scRNAseq) is a crucial tool in kidney research. These technologies cluster cells according to transcriptome similarity, irrespective of the anatomical location and ordering within the nephron. Thus, a cluster transcriptome may obscure heterogeneity of the cell population within a nephron segment. Elevated dietary fructose leads to salt-sensitive hypertension, in part by fructose reabsorption in the proximal tubule (PT). However, organization of the four known fructose transporters in apical PTs (SGLT4, SGLT5, GLUT5 and NaGLT1) remains poorly understood. We hypothesized that cells within each subsegment of the proximal tubule exhibit complex, heterogenous fructose transporter expression patterns. To test this hypothesis we analyzed rat and kidney transcriptomes and proteomes from publicly available scRNAseq and tubule microdissection databases. We found that microdissected PT-S1 segments consist of 81±12% cells with scRNAseq-derived transcriptional characteristics of S1, whereas PT-S2 express a mixture of 18±9% S1, 58±8% S2, and 19±5% S3 transcripts, and PT-S3 consists of 75±9% S3 transcripts. The expression of all four fructose transporters was detectable in all three PT segments, but key fructose transporters SGLT5 and GLUT5 progressively increased from S1 to S3, and both were significantly upregulated in S3 vs. S1/S2 (Slc5a10: 1.9 log2FC, p<1×10-299; Scl2a5: 1.4 log2FC, p<4×10-105). A similar distribution was found in human kidneys. These data suggest that S3 is the primary site of fructose reabsorption in both humans and rats. Finally, because of the multiple scRNAseq transcriptional phenotypes found in each segment our findings also imply that anatomic labels applied to scRNAseq clusters may be misleading.

show abstract

Section: Discussionmentioning

confidence: 99%

Profiling cellular heterogeneity and fructose transporter expression in the rat nephron by integrating single-cell and microdissected tubule segment transcriptomes

Zhang,

Jadhav,

Kramer

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The proximal tubule of the kidney expresses abundant Na + antiporters and Na + -dependent glucose or HCO 3 cotransporters, as well as Na + /K + -ATPase, that contribute to maintaining physiological proximal tubule function [4][5][6][7][8][9][10]. On the apical membrane side, NHE3 (Na + /H + exchanger 3), an ≈ 85-kDa protein encoded by the SLC9A3 gene, acts as a powerful driving force for directly and indirectly reabsorbing > 50% of the filtered Na + load in the proximal tubules [10][11][12][13]. The sodium and glucose cotransporter 2 (SGLT2), an ≈ 75-kDa protein encoded by the SLC5A2 (solute carrier family 5) gene, directly reabsorbs ~90% of filtered glucose in early S1 and S2 proximal tubules [5,11].…”

Section: Introductionmentioning

confidence: 99%

“…On the apical membrane side, NHE3 (Na + /H + exchanger 3), an ≈ 85-kDa protein encoded by the SLC9A3 gene, acts as a powerful driving force for directly and indirectly reabsorbing > 50% of the filtered Na + load in the proximal tubules [10][11][12][13]. The sodium and glucose cotransporter 2 (SGLT2), an ≈ 75-kDa protein encoded by the SLC5A2 (solute carrier family 5) gene, directly reabsorbs ~90% of filtered glucose in early S1 and S2 proximal tubules [5,11]. The enzyme carbonic anhydrase II converts CO 2 and H 2 O to H + and HCO 3 -, and the latter is then reabsorbed into the blood by the basolateral Na + /HCO 3 cotransporter NBCe1-A [1,2,6,14].…”

Section: Introductionmentioning

confidence: 99%

Intracellular Angiotensin II Stimulation of Sodium Transporter Expression in Proximal Tubule Cells via AT1 (AT1a) Receptor-Mediated, MAP Kinases ERK1/2- and NF-кB-Dependent Signaling Pathways

Zhuo

2023

Cells

View full text Add to dashboard Cite

The current prevailing paradigm in the renin-angiotensin system dictates that most, if not all, biological, physiological, and pathological responses to its most potent peptide, angiotensin II (Ang II), are mediated by extracellular Ang II activating its cell surface receptors. Whether intracellular (or intracrine) Ang II and its receptors are involved remains incompletely understood. The present study tested the hypothesis that extracellular Ang II is taken up by the proximal tubules of the kidney by an AT1 (AT1a) receptor-dependent mechanism and that overexpression of an intracellular Ang II fusion protein (ECFP/Ang II) in mouse proximal tubule cells (mPTC) stimulates the expression of Na+/H+ exchanger 3 (NHE3), Na+/HCO3- cotransporter, and sodium and glucose cotransporter 2 (Sglt2) by AT1a/MAPK/ERK1/2/NF-kB signaling pathways. mPCT cells derived from male wild-type and type 1a Ang II receptor-deficient mice (Agtr1a-/-) were transfected with an intracellular enhanced cyan fluorescent protein-tagged Ang II fusion protein, ECFP/Ang II, and treated without or with AT1 receptor blocker losartan, AT2 receptor blocker PD123319, MEK1/MEK2 inhibitor U0126, NF-кB inhibitor RO 106-9920, or p38 MAP kinase inhibitor SB202196, respectively. In wild-type mPCT cells, the expression of ECFP/Ang II significantly increased NHE3, Na+/HCO3-, and Sglt2 expression (p < 0.01). These responses were accompanied by >3-fold increases in the expression of phospho-ERK1/2 and the p65 subunit of NF-кB (p < 0.01). Losartan, U0126, or RO 106-9920 all significantly attenuated ECFP/Ang II-induced NHE3 and Na+/HCO3- expression (p < 0.01). Deletion of AT1 (AT1a) receptors in mPCT cells attenuated ECFP/Ang II-induced NHE3 and Na+/HCO3- expression (p < 0.01). Interestingly, the AT2 receptor blocker PD123319 also attenuated ECFP/Ang II-induced NHE3 and Na+/HCO3- expression (p < 0.01). These results suggest that, similar to extracellular Ang II, intracellular Ang II may also play an important role in Ang II receptor-mediated proximal tubule NHE3, Na+/HCO3-, and Sglt2 expression by activation of AT1a/MAPK/ERK1/2/NF-kB signaling pathways.

show abstract

“…SGLT2 is responsible for the renal reabsorption of 90% of filtered glucose. The rest is transported further downstream by sodium glucose transporter type 1 (SGLT1) [ 15 ]. However, blockade or knockout of SGLT2 only decreases glucose reabsorption by 30–50%, and not by 90%, as would be expected.…”

Section: Introductionmentioning

confidence: 99%

Sodium Glucose Cotransporter-2 Inhibitors: Spotlight on Favorable Effects on Clinical Outcomes beyond Diabetes

Chábová

Zakiyanov

2022

IJMS

View full text Add to dashboard Cite

Sodium glucose transporter type 2 (SGLT2) molecules are found in proximal tubules of the kidney, and perhaps in the brain or intestine, but rarely in any other tissue. However, their inhibitors, intended to improve diabetes compensation, have many more beneficial effects. They improve kidney and cardiovascular outcomes and decrease mortality. These benefits are not limited to diabetics but were also found in non-diabetic individuals. The pathophysiological pathways underlying the treatment success have been investigated in both clinical and experimental studies. There have been numerous excellent reviews, but these were mostly restricted to limited aspects of the knowledge. The aim of this review is to summarize the known experimental and clinical evidence of SGLT2 inhibitors’ effects on individual organs (kidney, heart, liver, etc.), as well as the systemic changes that lead to an improvement in clinical outcomes.

show abstract

Renal Tubular Handling of Glucose and Fructose in Health and Disease

Cited by 15 publications

References 418 publications

Profiling cellular heterogeneity and fructose transporter expression in the rat nephron by integrating single-cell and microdissected tubule segment transcriptomes

Profiling cellular heterogeneity and fructose transporter expression in the rat nephron by integrating single-cell and microdissected tubule segment transcriptomes

Intracellular Angiotensin II Stimulation of Sodium Transporter Expression in Proximal Tubule Cells via AT1 (AT1a) Receptor-Mediated, MAP Kinases ERK1/2- and NF-кB-Dependent Signaling Pathways

Sodium Glucose Cotransporter-2 Inhibitors: Spotlight on Favorable Effects on Clinical Outcomes beyond Diabetes

Contact Info

Product

Resources

About