Enhanced Intrarenal pro-renin and salt sensitive hypertension in a mouse model of Type-1 diabetes

Abstract

Hypertension affects up to 50% of patients with type 1 diabetes. Despite aggressive anti-hypertensive therapy, at least 30% of diabetic patients develop chronic kidney disease. Renin is the rate-limiting enzyme in the activation of the RAS and is essential for blood pressure control. Renin is expressed in Juxtaglomerular (JG) cells, as an immature pro-peptide (pro-renin), and then stored as active renin. In diabetic humans, plasma pro-renin is enhanced while renin remains unchanged or low. We hypothesize that intrarenal renin and pro-renin are enhanced in type 1 diabetes, which could potentially contribute to hypertension and diabetic nephropathy. We used the Akita mice strain, one of the few mouse models of diabetes mellitus that shows features of the human disease including hypertension and kidney damage. We found that Akita mice had higher blood pressure as measured by tailcuff (mmHg: C57=109±2.8; Aki=120.6±2.5;p<0.05, n=6), plasma glucose (in mM: C57=7.71±23.9; Aki=23.2±2.3; p<0.01; n=4) and proteinuria (mg/24hrs: C57 18.2±3.1; Aki: 29.4±3.3; p<0.05; n=5) when compared to C57 (control). In addition, plasma renin was not changed in Akita mice (n=6; p= NS). Histological staining of kidney cuts with a renin antibody (recognizes both renin and pro-renin) showed overall decreased total renin expression in Akita mice (O.D C57: 46.6±1.5; Akita=30.7±3.5). Surprisingly, Western Blots of renal cortical lysates and JG cells showed that pro-renin (43-45 kDa) expression was 79±21% higher in male Akita diabetic mice (p<0.05), demonstrating increased intra-renal pro-renin in Akita. The mechanism driving the increase in pro-renin is unknown. We previously showed that ROS potently stimulate renin release from JG cells. We found that Akita mice have increased urinary isoprostanes, supporting higher kidney ROS (ng/24hrs: C57:3.5±0.6 Aki=6.0±0.8 p<0.05; n=5). We measured H202 levels by transducing primary JG cells in culture with the fluorescent H202 protein sensor HyPer and found that JG cells isolated from Akita mice had higher baseline levels of H202 (C57= 100, Akita=117±7%, p<0.05). An activated intrarenal RAS contributes to salt sensitive hypertension, and at least one third of diabetic patients are salt-sensitive. It is not known whether diabetic Akita mice are salt sensitive. Therefore, we tested the effect of a high salt diet on blood pressure in Akita and C57 mice measured by radiotelemetry. High salt increased systolic blood pressure (SBP) in Akita (from 109±5 to 138±6 mmHg, p<0.001) but not in control C57 (from 104±2 to 117±6 mmHg, NS). We conclude that intrarenal renin and pro-renin is enhanced in Akita mice which also exhibit salt sensitive hypertension. The mechanism may involve elevated superoxide and H202 levels within JG cells stimulating pro-renin expression and release. AHA-SDG; NIH-NIDDK-RO3 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.