Acid Loading Unmasks Glucose Homeostatic Instability in Proximal-Tubule-Targeted Insulin/Insulin-Like-Growth-Factor-1 Receptor Dual Knockout Mice

Aljaylani, Abdullah; Fluitt, Maurice B.; Piselli, Alexandra; Shepard, Blythe D.; Tiwari, Swasti; Ecelbarger, Carolyn M.

doi:10.33594/000000248

Cited by 8 publications

(8 citation statements)

References 42 publications

(63 reference statements)

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“…This decrease was absent in the KOMs; in fact, they showed a modest increase (consistent with our PT-select KO mice) [20]. We have also reported lower G6PC renal protein levels in mice with a PT-targeted dual InsR/Igf1R KO [32]. In that case, the reduction occurred in both the male and female KO mice.…”

Section: Discussionsupporting

confidence: 89%

Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice

Sohail

Akkawi

Rechter

et al. 2023

IJMS

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Insulin facilitates renal sodium reabsorption and attenuates gluconeogenesis. Sex differences in this regulation have not been well characterized. Using tetracycline-inducible Cre-lox recombination, we knocked out (KO) the insulin receptor (InsR) from the renal tubule in adult male (M) and female (F) mice (C57Bl6 background) with a paired box 8 (PAX8) promoter. Body weights were not affected by the KO, but mean kidney weights were reduced in the KO mice (13 and 3%, in M and F, respectively, relative to wild-type (WT) mice). A microscopic analysis revealed 25 and 19% reductions in the proximal tubule (PT) and cortical collecting duct cell heights, respectively, in KOMs relative to WTMs. The reductions were 5 and 11% for KOFs. Western blotting of renal cortex homogenates showed decreased protein levels for the β and γ subunits of the epithelial sodium channel (ENaC) and the sodium-potassium-2-chloride cotransporter type 2 (NKCC2) in both sexes of KO mice; however, α-ENaC was upregulated in KOMs and downregulated in KOFs. Both sexes of KO mice cleared exogenously administered glucose faster than the WT mice and had lower semi-fasted, anesthetized blood glucose levels. However, KOMs (but not KOFs) demonstrated evidence of enhanced renal gluconeogenesis, including higher levels of renal glucose-6-phosphatase, the PT’s production of glucose, post-prandial blood glucose, and plasma insulin, whereas KOFs exhibited downregulation of renal high-capacity sodium glucose cotransporter (SGLT2) and upregulation of SGLT1; these changes appeared to be absent in the KOM. Overall, these findings suggest a sex-differential reliance on intact renal tubular InsR signaling which may be translationally important in type 2 diabetes, obesity, or insulin resistance when renal insulin signaling is reduced.

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Section: Discussionsupporting

confidence: 89%

Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice

Sohail

Akkawi

Rechter

et al. 2023

IJMS

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“…Kidney cortex homogenates were prepared into a sucrose/triethanolamine buffer containing protease inhibitors (HALT, ThermoFisher Scientific, Waltham, MA, USA) as we have previously described [ 14 ]. Western blots were conducted by loading and electrophoresing 20 μg protein in each lane of a BioRad (Hercules, CA, USA) 8–16% polyacrylamide gel, then blotting onto a 0.4 μm nitrocellulose membrane (BioRad).…”

Section: Methodsmentioning

confidence: 99%

Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration

et al. 2022

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Sodium glucose cotransporter, type 2 inhibitors, such as Empagliflozin, are protective of the kidneys by unclear mechanisms. Our aim was to determine how Empagliflozin affected kidney cortical metabolome and lipidome in mice. Adult male TALLYHO mice (prone to obesity) were treated with a high-milk-fat diet, or this diet containing Empagliflozin (0.01%), for 8 weeks. Targeted and untargeted metabolomics and lipidomics were conducted on kidney cortex by liquid chromatography followed by tandem mass-spectroscopy. Metabolites were statistically analyzed by MetaboAnalyst 5.0, LipidSig (lipid species only) and/or CEU Mass Mediator (untargeted annotation). In general, volcano plotting revealed oppositely skewed patterns for targeted metabolites (primarily hydrophilic) and lipids (hydrophobic) in that polar metabolites showed a larger number of decreased species, while non-polar (lipids) had a greater number of increased species (>20% changed and/or raw p-value < 0.05). The top three pathways regulated by Empagliflozin were urea cycle, spermine/spermidine biosynthesis, and aspartate metabolism, with an amino acid network being highly affected, with 14 of 20 classic amino acids down-regulated. Out of 75 changed polar metabolites, only three were up-regulated, i.e., flavin mononucleotide (FMN), uridine, and ureidosuccinic acid. Both FMN and uridine have been shown to be protective of the kidney. Scrutiny of metabolites of glycolysis/gluconeogenesis/Krebs cycle revealed a 20–45% reduction in several species, including phosphoenolpyruvate (PEP), succinate, and malic acid. In contrast, although overall lipid quantity was not higher, several lipid species were increased by EMPA, including those of the classes, phosphatidic acids, phosphatidylcholines, and carnitines. Overall, these analyses suggest a protection from extensive metabolic load and the corresponding oxidative stress with EMPA in kidney. This may be in response to reduced energy demands of the proximal tubule as a result of inhibition of transport and/or differences in metabolic pools available for metabolism.

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“…The sterol regulatory element binding protein-1 (SREBP-1) increases lipid droplet deposition in renal tubular cells and interstitial extracellular mechanisms ( 44 – 46 ), leading to tubular atrophy and interstitial fibrosis. Insulin like growth factor-1 (IGF-1) and dedifferentiation of vascular smooth muscle cells can induce connected tissue growth factor (CTGF), thus promoting renal tubular fibrosis Hyperglycemia in rat mesangial cells inhibits the degradation of the extracellular matrix by metalloproteinase 9, resulting in mesangial extracellular matrix proliferation and fibrosis ( 47 – 50 ). In addition, insulin resistance damages the microvessels of patients, especially the fundus, kidneys, muscles and cardiac arteries, and eventually damages the corresponding target organs ( 51 ).…”

Section: The Pathogenesis Of Mets-related Renal Injurymentioning

confidence: 99%

Metabolic Syndrome-Related Kidney Injury: A Review and Update

Tan

Pan

et al. 2022

Front. Endocrinol.

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Metabolic syndrome (MetS) includes visceral obesity, hyperglycemia, dyslipidemia, and hypertension. The prevalence of MetS is 20-25%, which is an important risk factor for chronic kidney disease (CKD). MetS causes effects on renal pathophysiology, including glomerular hyperfiltration, RAAS, microalbuminuria, profibrotic factors and podocyte injury. This review compares several criteria of MetS and analyzes their differences. MetS and the pathogenesis of CKD includes insulin resistance, obesity, dyslipidemia, inflammation, oxidative stress, and endothelial dysfunction. The intervention of MetS-related renal damage is the focus of this article and includes controlling body weight, hypertension, hyperglycemia, and hyperlipidemia, requiring all components to meet the criteria. In addition, interventions such as endoplasmic reticulum stress, oxidative stress, gut microbiota, body metabolism, appetite inhibition, podocyte apoptosis, and mesenchymal stem cells are reviewed.

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Acid Loading Unmasks Glucose Homeostatic Instability in Proximal-Tubule-Targeted Insulin/Insulin-Like-Growth-Factor-1 Receptor Dual Knockout Mice

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 8 publications

References 42 publications

Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice

Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice

Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration

Metabolic Syndrome-Related Kidney Injury: A Review and Update

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