Cross talk between the various systems is

Cross talk between the various systems is apparent with several well-described interactions such as that between C4-binding protein (C4BP) that regulates complement by inhibiting the classical initiation pathway and protein S, the latter being a cofactor for activated protein C, a regulator of coagulation and inflammation. There are and data that suggest coagulation cascade enzymes such as thrombin could cleave C5, carrying out the same reactions as the C5 convertase (). The cleavage products, however, did not directly generate C5a (). A new study () shows in a venous stasis model that C5a correlates strongly with clot weight implying that pathways initiated during clot formation lead to C5 cleavage. In contrast, there is a very weak correlation with thrombin–antithrombin complexes, suggesting that thrombin is not directly cleaving C5. They then investigated the ability of thrombin, factor Xa and plasmin to cleave C5 by measuring formation of C5a by ELISA. Plasmin, the effector enzyme in the fibrinolytic cascade, was the only enzyme that was able to cleave complement C5 at a similar rate as the canonical C5 convertase formed from complement components. The resultant C5b can assemble into the next stage of the terminal pathway, C5b,6, showing that the C5b generated by plasmin cleavage is functional in assembling the membrane attack complex.
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic disorders, occurring in approximately 1 in every 1000 live births (). About 50% of people who inherit the mutation will develop chronic kidney disease (CKD), characterized by the development of multiple large cysts in both kidneys followed by functional decline and end-stage renal disease. While the genetic mutations in polycystin 1 and polycystin 2 ( and , respectively) () were identified more than 30years ago, the mechanism of disease development remains largely unknown (). Menezes et al. took an unbiased systems-biology approach to study gene function and report their results in the current issue of EBioMedicine (). The authors performed genome wide transcript profiling on mice with conditional FRAX597 of , a model of ADPKD. They noted that disease severity was much milder in female mice when compared to their male counterparts. Metabolic genes represented the largest differentially expressed gene cluster, which correlated with disease development. Specifically, they identified differences in expression levels of several important regulators of lipid metabolism, which they probed further with unbiased metabolomics and lipidomics studies. Lipidomics studies highlighted several significant differences between control and knockout animals, including significantly lower diacylglycerol levels in mutant kidneys. Diacylglycerol is a byproduct of triglyceride metabolism. This prompted the authors to take a closer look at fatty acid oxidation. Cell culture studies showed that renal epithelial cells lacking have a cell autonomous defect in fatty acid oxidation, as these cells not oxidize palmitate as efficiently as control cells. Even though previous studies indicated changes in glucose metabolism in ADPKD, specifically an increased reliance on glucose as an energy source (), Menezes et al. were unable to detect changes in the glycolytic capacities of ADPKD cells. Throughout the body, specific tissues and cells have evolved individualized metabolic patterns. Tubular epithelial cells in the kidney require large amounts of energy, mostly to reabsorb filtered electrolytes and to eliminate potential toxins. This process has a high energy demand. Although constituting only 0.5% of body mass, kidneys consume 10% of the oxygen. To fuel this high energy consumption, tubule epithelial cells preferentially take up and oxidize fatty acids as their energy source and have a very high mitochondrial density (). Gene expression studies performed on microdissected tubule samples obtained from patients with (diabetic and hypertensive) chronic kidney disease (CKD) compared to healthy subjects highlighted that fatty acid metabolism is altered in human CKD samples (). In addition, cell culture studies indicate that CKD tubule cells are unable to switch to alternative fuel source such as glucose to efficiently generate energy. When lacking in energy, tubule cells are left dedifferentiated, unable to perform energy-demanding transport functions. Results of the present study indicate that the defect in lipid metabolism is not specific for a CKD type and most likely can be seen in all forms CKD.