Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D

Abstract

Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif −/− ) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif −/− mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif −/− as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H 2 O 2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.

Regulation of Vascular Function and Inflammation via Cross Talk of Reactive Oxygen and Nitrogen Species from Mitochondria or NADPH Oxidase—Implications for Diabetes Progression

“…Initial evidence for a cross talk between different sources of ROS in the setting of diabetes comes from the observation that diabetic complications are prevented by specific inhibitors of single ROS sources (Table 1). Unfortunately, targeting the mPTP by CypD knockout in the setting of diabetes did not prevent diabetic renal damage [239], representing a drawback for the hypothesis that we have put forward above. Finally, also a cross talk between oxidative stress and inflammation may be expected in the setting of diabetes, as markers of inflammation are increased in diabetic patients [240,241].…”

The Effect of S-15176 Difumarate Salt on Ultrastructure and Functions of Liver Mitochondria of C57BL/6 Mice with Streptozotocin/High-Fat Diet-Induced Type 2 Diabetes

“…Recent reports implicate that S-15176 difumarate salt exerts a number of effects on mitochondria. As shown by in vivo and in vitro studies, the drug can suppress the activity of mitochondrial CPT-1, the opening of the MPT pore, and overproduction of ROS by mitochondria [ 19 , 20 , 21 , 22 , 23 ]. So, the next objective of our work was to examine how this compound would affect the structural alterations in liver mitochondria of mice with T2DM.…”

“…It is well established that mitochondria of the liver are one of the main intracellular targets in the course of the development of T2DM [ 3 , 4 ]. The trimetazidine derivative S-15176 was reported to have diverse effects on mitochondria: the compound inhibits CPT-1, exhibits uncoupling and antioxidant properties, and suppresses the MPT pore opening [ 19 , 20 , 21 , 22 , 23 ]. Based on the above, we hypothesized that this compound would affect the mitochondrial function during the development of type 2 diabetes.…”

“…Another therapeutic strategy for the management of diabetes and obesity may be to use the mitochondrial uncoupling agents, which can contribute to both the suppression of increased ROS production by mitochondria and the loss of body weight [ 11 , 12 , 18 ]. The specific blockers of the mitochondrial permeability transition (MPT) pore were also tested as potential antidiabetic compounds [ 13 , 19 ].…”

Cardiac overexpression of microRNA-7 is associated with adverse cardiac remodeling

“…Critically, three of the downregulated proteins in miRNA-7 Tg hearts are localized to mitochondria (GHITM, NLRX1 and PPIF). PPIF codes for cyclophin D whose inhibition is considered to beneficial [26] and PPIF is already downregulated in miRNA-7Tg mice indicating that despite its loss these mice undergo adverse remodeling. However, less is known about the roles of NLRX1 or GHITM.…”