Hyperglycemia Induced by Chronic Intraperitoneal and Oral Glucose Loading Leads to Hypertension through Proximal Tubule Oxidative Stress‐ and Angiotensin II‐Mediated Na+‐Retention
Authors: Fakhruddin Selim , Alanazi Wael , Jackson Keith E. 
Published: November 2023

Feeding animals glucose, fructose, sucrose, or fat‐enriched diets for a period of time can lead to the development of hyperglycemia. Hyperglycemia resulting from such dietary intervention can promote a cluster of common complications including hypertension, insulin resistance, obesity, and dyslipidemia; all of which are defining factors of metabolic syndrome and can predispose individuals to the risk of developing stroke, heart failure, atherosclerosis, type 2 diabetes, diabetic retinopathy, and nephropathy. Severity of diet‐induced hyperglycemia largely depends on type and concentration of nutrients used and length of dietary intervention. In our current study, we used 4 groups of Sprague Dawley rats: control, glucose‐treated, tempol‐treated, and captopril‐treated groups. For all groups with the exception of the control, we used glucose‐enriched diet, drinking water, and intraperitoneal (ip) glucose injections to promote a sustained elevation in blood glucose throughout the two‐week study. We found that glucose levels gradually started to increase from day 3, and reached a peak level (321 mg/dl) at day 12 through day 14 in the glucose alone treated‐group compared to control. However, tempol‐ and captopril‐treated groups showed significantly high glucose levels in only the second week. Plasma insulin levels were significantly increased in glucose‐treated animals but not in tempol‐ and captopril‐treated groups when copared to control. We also observed significantly increased blood pressure (via tail‐cuff) from day 3 through day 12, whereas tempol‐ and captopril‐treated groups showed normal blood pressure (BP). Similarly, increased blood pressures (measured via in‐line Biopac system) were also found in anesthetized animals with no significant alterations in heart rate. Our findings also show increased Ang II production from 0.05 ng/ml to 0.12 ng/ml (control vs glucose) in interstitial fluid of the kidney cortex with a concomittant increase in oxidative stress via increased generation of superoxide and peroxinitrite free radicals. Ang II and/or oxidative stress can induce hypertension since both captopril and tempol treatments attenuated the elevation in BP. Moreover, urine flow was decreased from 5.7 μl/min in control to 2.35 μl/min in the glucose group whereas it was significantly increased in both tempol (5.68 μl/min) and captopril‐treated (6.9 μl/min) groups suggesting Na+‐retetion to be implicated in the observed elevation in BP. Na+‐retention may be, at least in part, mediated by renal upregulation of oxidative stress and Ang II. Interestingly, increased sodium reabsorption may happen through the proximal tubule of the nephron which is evident from our observation that proximal tubule (PT) specific α‐subunit of Na+‐K+‐ATPase is overexpressed in the glucose group. An upregulation of Na+‐K+‐ATPase can increase pumping of Na+ from interior sites of epithelial cells in the basolateral membrane of the PT to the interstitial fluid followed by increased Na+ reabsorption into the peritubular capillaries. As a result, it significantly increases Na+‐levels in plasma leading to increased blood volume and eventual hypertension.