Article Text
Abstract
Introduction Diabetic hyperglycemia causes progressive and generalized damage to the microvasculature. In renal glomeruli, this results in the loss of podocytes with consequent loss of constitutive angiopoietin-1 (Ang1) signaling, which is required for stability of the glomerular endothelium. Repeated tail vein injection of adenovirus expressing COMP-Ang1 (a stable bioengineered form of Ang1) was previously reported to improve diabetic glomerular damage despite the liver and lungs being primary targets of adenoviral infection. We thus hypothesized that localizing delivery of sustained COMP-Ang1 to the kidney could increase its therapeutic efficacy and safety for the treatment of diabetes.
Research design and methods Using AAVrh10 adeno-associated viral capsid with enhanced kidney tropism, we treated 10-week-old uninephrectomized db/db mice (a model of type 2 diabetes) with a single dose of AAVrh10.COMP-Ang1 delivered via the intracarotid artery, compared with untreated diabetic db/db control and non-diabetic db/m mice.
Results Surprisingly, both glomerular and pancreatic capillaries expressed COMP-Ang1, compensating for diabetes-induced loss of tissue Ang1. Importantly, treatment with AAVrh10.COMP-Ang1 yielded a significant reduction of glycemia (blood glucose, 241±193 mg/dL vs 576±31 mg/dL; glycosylated hemoglobin, 7.2±1.5% vs 11.3±1.3%) and slowed the progression of albuminuria and glomerulosclerosis in db/db mice by 70% and 61%, respectively, compared with untreated diabetic db/db mice. Furthermore, COMP-Ang1 ameliorated diabetes-induced increases of NF-kBp65, nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-2 (Nox2), p47phox and productions of myeloperoxidase, the inflammatory markers in both renal and pancreatic tissues, and improved beta-cell density in pancreatic islets.
Conclusions These results highlight the potential of localized Ang1 therapy for treatment of diabetic visceropathies and provide a mechanistic explanation for reported improvements in glucose control via Ang1/Tie2 signaling in the pancreas.
- experimental diabetes
- nephropathy
- pancreatic
- endothelial dysfunction
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Footnotes
Contributors MT, LSC and LT performed the experimental study, sample collection and analyses of samples. LT edited the manuscript. HU constructed the vector of the plasmids and measured plasma COMP-Ang1 levels. CW helped design and discuss the study. BKA designed the study, analysed the results and edited the manuscript. YH designed and performed the experimental study, sample collection and analyses of samples; wrote and edited the manuscript; and is the guarantor of this work and, as such, had full access to all the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the manuscript.
Funding This work was supported by the American Heart Association (No. 16GRNT27610030) (YH) and the American Diabetes Association (number 1-17-IBS-312) (YH). This work was also partially supported by NEI RO1 EY026029 (BKA) and RPB Unrestricted Grant (BKA). LT was the recipient of postdoctoral fellowship grant from Center of Kidney Transplantation, Ningbo Urology and Nephrology Hospital, Ningbo, Zhejiang, China.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. Data will be shared in the form of local and regional presentations and manuscript publications that will be publically available to all individuals in the scientific community. We will willingly share our knowledge, protocol, and expertise when asked. Requests for commercially based corporations will be negotiated by our institution’s Technology Transfer Office.