MicroRNA-29b inhibits diabetic nephropathy in db/db mice.
Inflammation and its consequent fibrosis are two main features of diabetic nephropathy (DN), but target therapy on these processes for DN remains yet ineffective. We report here that miR-29b is a novel therapeutic agent capable of inhibiting progressive renal inflammation and fibrosis in type 2 diabetes in db/db mice. Under diabetic conditions, miR-29b was largely downregulated in response to advanced glycation end (AGE) product, which was associated with upregulation of collagen matrix in mesangial cells via the transforming growth factor-β (TGF-β)/Smad3-dependent mechanism. These pathological changes were reversed by overexpressing miR-29b, but enhanced by knocking-down miR-29b. Similarly, loss of renal miR-29b was associated with progressive diabetic kidney injury, including microalbuminuria, renal fibrosis, and inflammation. Restored renal miR-29b by the ultrasound-based gene therapy was capable of attenuating diabetic kidney disease. Further studies revealed that inhibition of Sp1 expression, TGF-β/Smad3-dependent renal fibrosis, NF-κB-driven renal inflammation, and T-bet/Th1-mediated immune response may be mechanisms associated with miR-29b treatment in db/db mice. In conclusion, miR-29b may play a protective role in diabetic kidney disease and may have therapeutic potential for diabetic kidney complication.
Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Hai-Yong
HY
Chen
Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Xiang
X
Zhong
1] Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China [2] CUHK Shenzhen Research Institute, Shenzhen, The Chinese University of Hong Kong, Hong Kong, China.
Xiao R
XR
Huang
Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Xiao-Ming
XM
Meng
Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Yongke
Y
You
1] Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China [2] CUHK Shenzhen Research Institute, Shenzhen, The Chinese University of Hong Kong, Hong Kong, China.
Arthur Ck
AC
Chung
1] Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China [2] CUHK Shenzhen Research Institute, Shenzhen, The Chinese University of Hong Kong, Hong Kong, China.
Hui Y
HY
Lan
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000628:therapy*; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics / Q000628:therapy; D015316:Genetic Therapy; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000627:therapeutic use*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta