Stimulatory effect of insulin on renal proximal tubule sodium transport is preserved in type 2 diabetes with nephropathy

MicroRNAs (miRNAs) are short non-coding RNA species that are important post-transcriptional regulators of gene expression. The aim of the study was to establish a potential explanation of podocyte damage and proximal tubule (PT) dysfunction induced by deregulated miRNAs expression in the course of type 2 diabetes mellitus (DM). A total of 68 patients with type 2 DM and 11 healthy subjects were enrolled in a cross-sectional study and assessed concerning urinary albumin:creatinine ratio (UACR), urinary N-acetyl-β-D-glucosamininidase (NAG), urinary kidney injury molecule-1, urinary nephrin, podocalyxin, synaptopodin, estimated glomerular filtration rate (eGFR), urinary miRNA21, miRNA124, and miRNA192. In univariable regression analysis, miRNA21, miRNA124, and miRNA192 correlated with urinary nephrin, synaptopodin, podocalyxin, NAG, KIM-1, UACR, and eGFR. Multivariable regression analysis yielded models in which miRNA192 correlated with synaptopodin, uNAG, and eGFR (R2=0.902; P<0.0001), miRNA124 correlated with synaptopodin, uNAG, UACR, and eGFR (R2=0.881; P<0.0001), whereas miRNA21 correlated with podocalyxin, uNAG, UACR, and eGFR (R2=0.882; P<0.0001). Urinary miRNA192 expression was downregulated, while urinary miRNA21 and miRNA124 expressions were upregulated. In patients with type 2 DM, there is an association between podocyte injury and PT dysfunction, and miRNA excretion, even in the normoalbuminuria stage. This observation documents a potential role of the urinary profiles of miRNA21, miRNA124, and miRNA192 in early DN. Despite their variability across the segments of the nephron, urinary miRNAs may be considered as a reliable tool for the identification of novel biomarkers in order to characterize the genetic pattern of podocyte damage and PT dysfunction in early DN of type 2 DM.

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Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells

Journal of the American Society of Hypertension ◽

10.1016/j.jash.2017.11.009 ◽

2018 ◽

Vol 12 (2) ◽

pp. 135-145 ◽

Cited By ~ 2

Author(s):

Yang Yang ◽

Caiyu Chen ◽

Chunjiang Fu ◽

Zaicheng Xu ◽

Cong Lan ◽

...

Keyword(s):

Angiotensin Ii ◽

Proximal Tubule ◽

Insulin Receptor ◽

Renal Proximal Tubule ◽

Proximal Tubule Cells ◽

Rat Renal Proximal Tubule ◽

Tubule Cells ◽

Renal Proximal Tubule Cells ◽

And Function

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Interactions between gluconeogenesis and sodium transport in rabbit proximal tubule

AJP Renal Physiology ◽

10.1152/ajprenal.1984.246.6.f859 ◽

1984 ◽

Vol 246 (6) ◽

pp. F859-F869 ◽

Cited By ~ 2

Author(s):

S. R. Gullans ◽

P. C. Brazy ◽

V. W. Dennis ◽

L. J. Mandel

Keyword(s):

Proximal Tubule ◽

Sodium Transport ◽

Acid Metabolism ◽

Renal Proximal Tubule ◽

Active Sodium ◽

Atp Production ◽

Cellular Energy ◽

Glucose Synthesis ◽

And Control ◽

Gluconeogenic Substrate

Gluconeogenesis and sodium transport are ATP-requiring functions of the renal proximal tubule. Previously observed interactions between these processes indicated that they may compete for cellular energy. We have reevaluated this interaction in the rabbit proximal tubule using two preparations: suspensions of cortical tubules and isolated perfused tubules. In the presence of lactate and alanine, net glucose synthesis was 22.3 +/- 1.3 nmol X mg protein-1 .30 min-1. Additions of valerate, butyrate, or succinate increased this rate by factors of 2-3 without affecting cellular ATP levels or net fluid absorption (Jv). Inhibition of ATP production with rotenone, which we have previously shown to inhibit Jv [Am. J. Physiol. 243 (Renal Fluid Electrolyte Physiol. 12): F133-F140, 1982], greatly decreased the gluconeogenic rate, but this was modulated by the type of gluconeogenic substrate used. Increasing Na-K-ATPase activity with nystatin or decreasing it with ouabain had widely differing effects, which also depended on the substrate regimen. We conclude that the interaction between gluconeogenesis and active sodium transport cannot be described by a simple competition for ATP. Rather, under normal circumstances, the renal proximal tubule can meet the energetic demands of both gluconeogenesis and sodium transport, and control of these processes is multifactorial and sensitive to fatty acid metabolism.

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Renal olfactory receptor 1393 contributes to the progression of type 2 diabetes in a diet-induced obesity model

AJP Renal Physiology ◽

10.1152/ajprenal.00069.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. F372-F381 ◽

Cited By ~ 11

Author(s):

Blythe D. Shepard ◽

Hermann Koepsell ◽

Jennifer L. Pluznick

Keyword(s):

Type 2 Diabetes ◽

Proximal Tubule ◽

High Fat Diet ◽

Olfactory Receptor ◽

Early Stage ◽

Fasting Blood Glucose ◽

Olfactory Receptors ◽

High Fat ◽

Glucose Reabsorption

Olfactory receptors are G protein-coupled receptors that serve to detect odorants in the nose. Additionally, these receptors are expressed in other tissues, where they have functions outside the canonical smell response. Olfactory receptor 1393 (Olfr1393) was recently identified as a novel regulator of Na+-glucose cotransporter 1 (Sglt1) localization in the renal proximal tubule. Glucose reabsorption in the proximal tubule (via Sglt1 and Sglt2) has emerged as an important contributor to the development of diabetes. Inhibition of Sglt2 is accepted as a viable therapeutic treatment option for patients with type 2 diabetes and has been shown to delay development of diabetic kidney disease. We hypothesized that Olfr1393 may contribute to the progression of type 2 diabetes, particularly the development of hyperfiltration, which has been linked to increased Na+ reabsorption in the proximal tubule via the Sglts. To test this hypothesis, Olfr1393 wild-type (WT) and knockout (KO) mice were challenged with a high-fat diet to induce early-stage type 2 diabetes. After 16 wk on the high-fat diet, fasting blood glucose values were increased and glucose tolerance was impaired in the male WT mice. Both of these effects were significantly blunted in the male KO mice. In addition, male and female WT mice developed diabetes-induced hyperfiltration, which was attenuated in the Olfr1393 KO mice and corresponded with a reduction in luminal expression of Sglt2. Collectively, these data indicate that renal Olfr1393 can contribute to the progression of type 2 diabetes, likely as a regulator of Na+-glucose cotransport in the proximal tubule.

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Therapy with atorvastatin versus rosuvastatin reduces urinary podocytes, podocyte-associated molecules, and proximal tubule dysfunction biomarkers in patients with type 2 diabetes mellitus: a pilot study

Renal Failure ◽

10.1080/0886022x.2016.1254657 ◽

2016 ◽

Vol 39 (1) ◽

pp. 112-119 ◽

Cited By ~ 8

Author(s):

Adrian Vlad ◽

Mihaela Vlad ◽

Ligia Petrica ◽

Sorin Ursoniu ◽

Florica Gadalean ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Pilot Study ◽

Proximal Tubule

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Abstract P2047: Human Renal Proximal Tubule Cells Cultured Under High Salt Conditions Increase Angiotensin Type 2 Receptor Abundance In Secreted Exosomes

Hypertension ◽

10.1161/hyp.74.suppl_1.p2047 ◽

2019 ◽

Vol 74 (Suppl_1) ◽

Author(s):

Nicholas C Laterza ◽

John J Gildea ◽

Peng Xu ◽

Katherine A Schiermeyer ◽

Robin A Felder

Keyword(s):

Proximal Tubule ◽

Renal Proximal Tubule ◽

High Salt ◽

Proximal Tubule Cells ◽

Angiotensin Type 2 Receptor ◽

Tubule Cells ◽

Renal Proximal Tubule Cells ◽

Angiotensin Type ◽

Cells Cultured

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Renal tubular effects of prolonged therapy with the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes mellitus

AJP Renal Physiology ◽

10.1152/ajprenal.00432.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. F231-F240 ◽

Cited By ~ 7

Author(s):

Lennart Tonneijck ◽

Marcel H. A. Muskiet ◽

Charles J. Blijdorp ◽

Mark M. Smits ◽

Jos W. Twisk ◽

...

Keyword(s):

Diabetes Mellitus ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Urinary Excretion ◽

Proximal Tubule ◽

Urinary Ph ◽

Renal Tubular ◽

Insulin Glulisine

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are well-established glucose-lowering drugs for type 2 diabetes mellitus (T2DM) management. Acute GLP-1RA administration increases urinary excretion of sodium and other electrolytes. However, the renal tubular effects of prolonged GLP-1RA treatment are largely unknown. In this secondary analysis of a randomized trial, we determined the renal tubular effects of 8-wk treatment with 20 μg lixisenatide, a short-acting (prandial) GLP-1RA, versus titrated once-daily insulin glulisine in 35 overweight T2DM-patients on stable insulin glargine background therapy (age: 62 ± 7 yr, glycated hemoglobin: 8.0 ± 0.9%, estimated glomerular filtration rate: >60 ml·min−1·1.73 m−2). After a standardized breakfast, lixisenatide increased absolute and fractional excretions of sodium, chloride, and potassium and increased urinary pH. In contrast, lixisenatide reduced absolute and fractional excretions of magnesium, calcium, and phosphate. At week 8, patients treated with lixisenatide had significantly more phosphorylated sodium-hydrogen exchanger isoform 3 (NHE3) in urinary extracellular vesicles than those on insulin glulisine treatment, which suggested decreased NHE3 activity in the proximal tubule. A rise in postprandial blood pressure with lixisenatide partly explained the changes in the urinary excretion of sodium, potassium, magnesium, and phosphate and the changes in urinary pH. In conclusion, lixisenatide affects postprandial urinary excretion of several electrolytes and increases urinary pH compared with insulin glulisine in T2DM patients after 8 wk of treatment. This is most likely explained by a drug-induced rise in blood pressure or direct inhibitory effects on NHE3 in the proximal tubule.

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