Blockade of the mitochondrial transition pore in diabetic kidney disease

Identification: Lindblom, Runa


Description

 

Blockade of the mitochondrial transition pore in diabetic kidney disease
 
Lindblom, R.S.J1, Higgins, G.C1, Forbes, J.M. 2, Cooper, M.E1, Coughlan, M.T1
1Department of Diabetes, Monash University, Melbourne, AU; 2Mater Medical Research Institute, Brisbane, AU
 
Diabetes Mellitus, including both type 1 (T1D) and type 2 (T2D), is one the most important global health issues of the 21st century. Approximately 30% of patients will develop diabetic kidney disease (DKD). Few effective therapies are available to slow the clinical progression of DKD to End Stage Renal Disease; which requires dialysis or renal replacement therapy. Much of the underlying aetiology of DKD remains unknown, however mitochondrial dysfunction is co-associated with the disease. Studies from our laboratory and others have shown a decline in mitochondrial function in the kidney in DKD, leading to ATP depletion, changes in mitochondrial morphology and renal fibrosis. In addition, a greater susceptibility to mitochondrial permeability transition (mPT) pore opening is observed.
In this study, we determined whether reducing mPT pore capacity would ameliorate diabetes-induced renal injury using both gene knockout and pharmacological strategies to directly interrupt mPT pore function. In study 1, we used mice with a genetic knockout of the functional unit of the pore, Cyclophilin D (Ppif -/-). Wild type and Ppif -/- mice (n=15/group) were rendered diabetic using streptozotocin (55mg/kg/day, a model of T1D) and followed for 20 weeks. In study 2, we used a mouse model of T2D, the db/db mouse. Db/db mice and their littermate controls (db/h) were randomized to receive a Cyclophilin D inhibitor, the non-immunosuppressive Cyclosporin A analogue - Alisporovir, by daily oral gavage for 16 weeks (10mg/kg/day) from 6 weeks of age.  
Glycemic control was unchanged for both the Diabetic Ppif -/- and Ppif WT STZ mice. Likewise, Alisporovir did not alter glycemic control in db/db mice and no change in body fat composition observed. Preliminary data shows that neither the genetic deletion of Cyclophilin D, nor therapeutic targeting of the protein using Alisporovir, reduced renal injury as observed by no statistically significant improvement in markers for glomerular and tubular injury. This study suggests that the mPT pore is not a suitable therapeutic target in DKD.
 
Funding provided by Diabetes Australia
 

Credits

Credits: None available.

You must be logged in and own this product in order to post comments.