α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions

Abstract

Diabetes mellitus (DM) causes high glucose (HG) levels in the plasma and urine. The (pro)renin receptor (PRR) is a key regulator of renal Na+ handling. PRR is expressed in intercalated (IC) cells of the collecting duct (CD) and binds renin to promote angiotensin (Ang) II formation, thereby contributing to Na+ reabsorption. In DM, the Kreb's cycle is in a state of suppression in most tissues. However, in the CD, expression of glucose transporters is augmented, boosting the Kreb's cycle and consequently causing α-ketoglutarate (αKG) accumulation. The αKG receptor 1 (OXGR1) is a Gq-coupled receptor expressed on the apical membrane of IC cells of the CD. We hypothesize that HG causes αKG secretion and activation of OXGR1, which increases PRR expression in CD cells. This effect then promotes intratubular AngII formation and Na+ reabsorption. To test this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with or without montelukast (ML), an OXGR1 antagonist, for 6 days. STZ mice had higher urinary αKG and PRR expression along with augmented urinary AngII levels and Na+ retention. Treatment with ML prevented all these effects. Similarly, primary cultured inner medullary CD cells treated with HG showed increased PRR expression, while OXGR1 antagonist prevented this effect. αKG increases PRR expression, while treatments with ML, PKC inhibition, or intracellular Ca2+ depletion impair this effect. In silico analysis suggested that αKG binds to mouse OXGR1. These results indicate that HG conditions promote increased levels of intratubular αKG and OXGR1-dependent PRR upregulation, which impact AngII formation and Na+ reabsorption.

Increased Renal Medullary NOX-4 in Female but Not Male Mice during the Early Phase of Type 1 Diabetes: Potential Role of ROS in Upregulation of TGF-β1 and Fibronectin in Collecting Duct Cells

“…All these symptoms are consistent with the clinical manifestation of DM in humans. Interestingly, determinations of Na + balance among the groups using a Na + challenge demonstrated a positive Na + balance on day 6 in male and female STZ mice; this is consistent with previous studies using this model [ 21 ]. Because of the impact that positive Na + balance may have on systolic blood pressure, we performed tail cuff—systolic blood pressure measurements in all groups.…”

“…As shown in Figure 2 A, the STZ mice were not able to recover control levels of FBG when compared to control animals. Since we previously demonstrated that STZ mice showed Na + retention [ 21 ], control and STZ mice were injected with isotonic saline (i.p. 10% of body weight) and placed in metabolic cages for urine measurements.…”

Activation of 2‐oxoglutarate receptor 1 (OXGR1) by α‐ketoglutarate (αKG) does not detectably stimulate Pendrin‐mediated anion exchange in Xenopus oocytes

“…AT1R is expressed throughout the nephron on both apical and basolateral membranes. aKG has been shown to upregulate both tubular angiotensin II biosynthesis and the plasma renin receptor that colocalizes with OXGR1 (Guerrero et al, 2021 ). Although Ca 2+ influx increased 8‐fold in response to bath addition of 100 nM angiotensin II, αKG‐dependent OXGR1‐stimulated Ca 2+ influx was not increased by AT1R coexpression (not shown).…”

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

“…STZ-induced type I diabetic rats show increased urinary levels of AKG, citrate, and succinate. In the kidney, high glucose conditions promote increased intratubular AKG and OXGR1-dependent AngII formation and Na + reabsorption [ 357 ].…”