IGF IIRα-triggered pathological manifestations in the heart aggravate renal inflammation in STZ-induced type-I diabetes rats

Abstract

Pathological manifestations in either heart or kidney impact the function of the other and form the basis for the development of cardiorenal syndrome. However, the mechanism or factors involved in such scenario are not completely elucidated. In our study, to find the correlation between late fetal gene expression in diabetic hearts and their influence on diabetic nephropathy, we created a rat model with cardiac specific overexpression of IGF-IIRα, which is an alternative splicing variant of IGFIIR, expressed in pathological hearts. In this study, transgenic rats over expressing cardiac specific IGF-IIRα and non-transgenic animal models established in SD rats were administered with single dose of streptozotocin (STZ, 55 mg/Kg) to induce Type I diabetes. The correlation between IGF-IIRα and kidney damages were further determined based on their intensity of damage in the kidneys. The results show that cardiac specific overexpression of IGF-IIRα elevates the diabetes associated inflammation and morphological changes in the kidneys. The diabetic transgenic rats showed advancement in the pathological features such a renal tubular damage, collagen accumulation and enhancement in STAT3 associated mechanism of renal fibrosis. The results therefore show that that IGF-IIRα expression in the heart during pathological condition may worsen symptoms of diabetic nephropathy in rats.

Insulin‐like growth factor II receptor alpha overexpression in heart aggravates hyperglycemia‐induced cardiac inflammation and myocardial necrosis

“…Both in vitro and in vivo models have shown that MAPK signaling hypertrophy and mitochondrial‐dependent apoptosis are activated; however, the PI3K‐AKT survival cascade is attenuated when IGF‐IIRα is specifically expressed in cardiomyocytes and cardiac tissues 43 . IGF‐IIRα overexpression in the heart not only causes pathological heart, but also leads to hypertrophic kidney, 44 liver, and testis (unpublished data) in the transgenic rats. In the diabetic transgenic rats, collagen accumulation, renal tubular damage, and renal fibrosis are present in the pathological kidney by enhancement of STAT3 associated mechanism 44 .…”

“…In the heart, chronic high‐blood glucose levels increase Toll‐like receptor 4 activation and induce downstream pathways, including the NF‐κB inflammatory pathway 22,46 . Additionally, cardiac specific overexpression of IGF‐IIRα elevates the diabetes related inflammation 44 . Hence, IGF‐IIRα may be an inflammation inducer.…”

“…In the diabetic transgenic rats, collagen accumulation, renal tubular damage, and renal fibrosis are present in the pathological kidney by enhancement of STAT3 associated mechanism. 44 It indicates that IGF-IIRα overexpression in the heart during pathological condition may be secreted into other organics and results in systemic symptoms in the transgenic rats.…”

“…22,46 Additionally, cardiac specific overexpression of IGF-IIRα elevates the diabetes related inflammation. 44 Hence, IGF-IIRα may be an inflammation inducer. In this study, NF-κB was activated, and its inhibitor…”