Diabetic nephropathy (DN) is a major diabetic complication that is mediated by transforming growth factor (TGF)‐β1
via Smad‐dependent and ‐independent signalling pathways.
Under diabetic conditions, many profibrotic factors, such as advanced glycation end‐products and angiotensin II,
can also activate the Smad signalling pathway via the extracellular signal‐regulated kinase/p38 mitogen‐activated protein kinase–Smad signalling cross‐talk pathway. Thus, Smads
act as signal integrators and interact with other signalling pathways to mediate DN.
In the context of renal fibrosis, Smad3 is pathogenic, but Smad2 is protective.
Deletion of Smad3 inhibits, whereas disruption of Smad2 upregulates, connective tissue growth factor and vascular endothelial growth factor expression and promotes both epithelial–myofibroblast and endothelial–myofibroblast
Smad7 plays a protective role in DN because deletion of Smad7 enhances, whereas overexpression of Smad7
inhibits, Smad3‐mediated renal fibrosis and nuclear factor‐κB‐driven renal inflammation.
Transforming growth factor‐β1 activates Smad3
to regulate microRNAs that mediate renal fibrosis. Of these, miR‐21 and miR‐192 are upregulated, whereas the miR‐29 and miR‐200 families are downregulated.
Targeting downstream TGF‐β/Smad signalling by overexpressing Smad7‐ or Smad3‐dependent microRNA
related to fibrosis may represent a novel and effective strategy for the treatment of DN.
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Document Type: Research Article
Publication date: August 1, 2012