TGF-beta/Smad signaling pathway in hypertensive kidney and cardiovascular diseases

This presentation was given by Hui Yao Lan from the Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, Hong Kong. It was presented at the ISN’s Forefronts Symposium 2015 taking place in Shenzhen, China, on October 22-25, 2015 for which the theme was ‘Immunomodulation of Cardio-Renal Function’ during Session 10: Key Signaling Pathways in Renal and Cardiovascular Disease.


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Presentation Abstract: 

TGF-beta/Smad signaling pathway in kidney and cardiovascular diseases 

Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR

It is now well accepted that TGF-?/Smad signaling is a major pathway leading to renal and cardiac fibrosis. We recently found under hypertensive conditions, angiotensin II is able to activate the TGF- ? /Smad signaling pathway via both TGF- ? -dependent and independent mechanisms. Under disease conditions, Smad3 is highly activated, which is associated with a loss of Smad7, an inhibitor of Smad2/3. The pathogenic role of Smad3 in renal and cardiac fibrosis and inflammation is examined in hypertensive cardio-renal disease induced in Smad3 by subcutaneous angiotensin II infusion. Results show that deletion of Smad3 prevents angiotensin II-mediated cardio-renal inflammation and fibrosis.

Next, we examined the mechanism by which Smad3 mediates cardio-renal fibrosis by RNA-seq and found that deletion of Smad3 prevents a loss of miR-29 family, suggesting that the miR-29 family is the downstream target of Smad3 and Smad3 mediates cardi0-renal fibrosis by downregulating miR-29 expression.

We next developed novel therapeutic strategies by targeting Smad3 signaling with overexpression of cardio-renal Smad7, or by restoring miR-29b. All therapeutic strategies demonstrate that blockade of Smad3 by overexpressing Smad7 is capable of inhibiting cardio-renal inflammation and fibrosis in a mouse model of hypertensive kidney and heart disease.  Interestingly, we also find that overexpression of miR-29b is able to block angiotensin II-induced cardiac fibrosis and diabetic nephropathy by inhibiting TGF- ? /Smad3 signaling, suggesting that the positive and negative feedback loop of TGF- ? /Smad3-miR-29 regulates cardi0-renal fibrosis. 

In summary, TGF- ? /Smad3 signaling is a key pathway leading to cardi0-renal fibrosis and targeting this pathway by overexpression of Smad7 or miR-29 may represent a novel and specific therapy for cardi0-renal fibrosis.

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