Abstract: FR-PO636

TRAM34, an Inhibitor of KCa3.1: A Novel Therapy for Treatment of Established Diabetic Nephropathy

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Huang, Chunling, kolling institute, the University of Sydney, Sydney, New South Wales, Australia
  • Zhang, Ling, kolling institute, the University of Sydney, Sydney, New South Wales, Australia
  • Yi, Hao, kolling institute, the University of Sydney, Sydney, New South Wales, Australia
  • Shi, Ying, kolling institute, the University of Sydney, Sydney, New South Wales, Australia
  • Chen, Xinming, kolling institute, the University of Sydney, Sydney, New South Wales, Australia
  • Pollock, Carol A., kolling institute, the University of Sydney, Sydney, New South Wales, Australia
Background

Existing treatments of established diabetic nephropathy have not been proven to have long term efficacy. Hence it is essential and indeed urgent to discover novel therapeutic targets to stabilize or reverse diabetic nephropathy. KCa3.1 is an intermediate/small-conductance calcium activated potassium channel. The most well defined role of KCa3.1 channels is to regulate calcium entry into cells and thereby modulate calcium-signaling processes. We have previously demonstrated in murine models of diabetes mellitus that gene silencing or pharmacological blockade of KCa3.1, when introduced at the induction of diabetes mellitus, confers significant protection against the subsequent development of diabetic induced interstitial fibrosis through inhibition of TGF-β1 signalling pathways. Therefore, this study aimed to investigate the therapeutic effect of the KCa3.1 inhibitor TRAM34 in a mouse model of established diabetic nephropathy.

Methods

Diabetic eNOS-/- mice with established nephropathy (24 weeks after induction of type 1 diabetes induced by streptozotocin) were treated with TRAM34 or DMSO (vehicle control) for a further 14 weeks. Preterminal kidney function and subsequent renal structure were assessed as well as inflammatory, fibrotic markers and the TGF-β1 signalling pathway.

Results

24h urinary albumin was significantly increased in the diabetic animals compared to the non-diabetic controls (P< 0.01). Albuminuria was significantly reduced in TRAM 34 treated diabetic animals compared to the diabetic group (P<0.05). Immunohistochemistry demonstrated increased CD68 and F4/80 expression, indicating increased macrophage infiltration in the diabetic animals (P< 0.05), which was reversed by treatment with TRAM34 (P< 0.05). Similarly, TRAM34 reversed the increased mRNA and protein expression of type I and type III collagen and fibronectin observed in the diabetic animals (P< 0.05). Furthermore, blocking the KCa3.1 channel by TRAM34 led to the reduction of TGF-β1 signaling through inhibiting phosphorylation of Smad2/3 (P< 0.05).

Conclusion

Blockade of KCa3.1 by TRAM34 is a promising therapeutic intervention in established diabetic nephropathy.

Funding

  • Private Foundation Support