Abstract
Uncontrolled activation of transforming growth factor beta (TGF-β) family members is hypothesized to participate in type 2 diabetes (T2D) dependent diabetic nephropathy (DN). We evaluated and compared downstream activation of the Smad2-signaling pathway in kidney samples from T2D patients to kidneys from the T2D model of leptin receptor deficient db/db mouse. Furthermore, expression of TGF-β family members was evaluated to elucidate molecular mechanisms in the mouse model. Kidney samples from patients with advanced stages of DN showed elevated pSmad2 staining whereas db/db mouse kidneys surprisingly showed a decrease in pSmad2 in the tubular compartment. Structurally, kidney tissue showed dilated tubules and expanded glomeruli, but no clear fibrotic pattern was found in the diabetic mice. Selective TGF-β family members were up-regulated at the mRNA level. Antagonists of bone morphogenetic protein (BMP) ligands, such as Gremlin1, USAG1 and Sclerostin, were strongly up-regulated suggesting a dampening effect on BMP pathways. Together, these results indicate a lack of translation from T2D patient kidneys to the db/db model with regards to Smad signaling pathway. It is plausible that a strong up-regulation of BMP antagonizing factors account for the lack of Smad1/5/8 activation, in spite of increased expression of several BMP members.
Highlights
Metabolic diseases such as obesity and type 2 diabetes (T2D) are closely linked, and 35% of the population is estimated overweight or obese in the Western world, a number which continues to increase [1]
diabetic nephropathy (DN) associated fibrosis is considered to involve an imbalance of the transforming growth factor beta (TGF-b) family activity causing elevated
Results on Smad staining within the field of kidney fibrosis are contradictory, which we suggest can be due to different mouse strains and the use of different anti-Smad antibodies directed against either phospho-Smad or Smad showing different affinity and degree of cross-reactivity
Summary
Metabolic diseases such as obesity and type 2 diabetes (T2D) are closely linked, and 35% of the population is estimated overweight or obese in the Western world, a number which continues to increase [1]. Obesity and T2D are associated with a higher risk of cardiovascular disease (CVD), decreased insulin sensitivity and chronic kidney disease (CKD), which increases mortality beyond the traditional CVD risk factors [2,3]. Obesity-related renal disease is similar to the microvascular damage observed in diabetic nephropathy (DN) [4]. It is believed that kidney damage is a consequence of a combination of increased glomerular capillary pressure and hyperfiltration, endothelial cell proliferation and dysfunction, increased vascular permeability, increased protein traffic, mesangial hyperplasia and renal hypertrophy [5,6]. T2D patients show larger variation in disease pattern and pathology, which complicates the study of DN within T2D as estimates for rate of disease progression are imprecise and sparse [8,9,10]
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