Abstract
Both diabetes and obesity (diabesity) contribute significantly to the development of chronic kidney disease (CKD). In search of new remedies to reverse or arrest the progression of CKD, we examined the therapeutic potential of a novel compound, AN1284, in a mouse model of CKD induced by type 2 diabetes with obesity. Six-week-old BKS Cg-Dock 7m+/+ Leprdb/J mice with type 2 diabetes and obesity were treated with AN1284 (2.5 or 5 mg kg−1 per day) via micro-osmotic pumps implanted subcutaneously for 3 months. Measures included renal, pancreatic, and liver assessment as well as energy utilization. AN1284 improved kidney function in BSK-db/db animals by reducing albumin and creatinine and preventing renal inflammation and morphological changes. The treatment was associated with weight loss, decreased body fat mass, increased utilization of body fat toward energy, preservation of insulin sensitivity and pancreatic β cell mass, and reduction of dyslipidemia, hepatic steatosis, and liver injury. This indoline derivative protected the kidney from the deleterious effects of hyperglycemia by ameliorating the metabolic abnormalities of diabetes. It could have therapeutic potential for preventing CKD in human subjects with diabesity.
Highlights
Over the past decades, diabetes and obesity have evolved into global epidemics, affecting social groups and ages in both developed and developing countries
We showed that type 2 diabetes in this model is associated with renal inflammation, as indicated by the increased protein expression of inflammatory markers MCP1, TNFα, TGFβ, and IL-18
The molecular mechanisms contributing to the development of chronic kidney disease (CKD) in diabetes and obesity are quite different, it is accompanied in each condition by glomerular hypertrophy and transient hyper-filtration, glomerular basement membrane thickening, and mesangial matrix expansion, resulting in albuminuria [20, 21]
Summary
Diabetes and obesity have evolved into global epidemics, affecting social groups and ages in both developed and developing countries. A new term used to describe the co-existence of these two conditions [1], results in the death of over a million people worldwide each year, and its global prevalence exceeds 347 million. It is the principal cause of cardiovascular disease, stroke, dementia, cancer, non-alcoholic fatty liver disease (NAFLD), and chronic kidney disease (CKD) [2]. The latter remains the leading cause of end-stage renal disease [1] and is responsible for the rise in mortality among diabetic patients [3, 4]. There is a critical need to develop more effective, long-lasting treatments for CKD
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