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BackgroundDiabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored.MethodsUsing hydrodynamic tail-vein injection, we overexpress Esm-1 in DKD-susceptible DBA/2 mice and delete Esm-1 in DKD-resistant C57BL/6 mice to study the contribution of Esm-1 to DKD. We analyze clinical indices of DKD, leukocyte infiltration, podocytopenia, and extracellular matrix production. We also study transcriptomic changes to assess potential mechanisms of Esm-1 in glomeruli.ResultsIn DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. We show that overexpression of Esm-1 reduces albuminuria and diabetes-induced podocyte injury, independent of changes in leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice modestly increases the degree of diabetes-induced albuminuria versus wild-type controls. By glomerular RNAseq, we identify that Esm-1 attenuates expression of kidney disease–promoting and interferon (IFN)-related genes, includingAckr2andCxcl11.ConclusionsWe demonstrate that, in DKD-susceptible mice, Esm-1 protects against diabetes-induced albuminuria and podocytopathy, possibly through select IFN signaling. Companion studies in patients with diabetes suggest a role of Esm-1 in human DKD.

Stent retriever thrombectomy is a pre-eminent treatment modality for large vessel ischaemic stroke. Simulation of thrombectomy could help understand stent and clot mechanics in failed cases and provide a digital testbed for the development of new, safer devices. Here, we present a novel, in silico thrombectomy method using a hybrid finite-element analysis (FEA) and smoothed particle hydrodynamics (SPH). Inspired by its biological structure and components, the blood clot was modelled with the hybrid FEA–SPH method. The Solitaire self-expanding stent was parametrically reconstructed from micro-CT imaging and was modelled as three-dimensional finite beam elements. Our simulation encompassed all steps of mechanical thrombectomy, including stent packaging, delivery and self-expansion into the clot, and clot extraction. To test the feasibility of our method, we simulated clot extraction in simple straight vessels. This was compared against in vitro thrombectomies using the same stent, vessel geometry, and clot size and composition. Comparisons with benchtop tests indicated that our model was able to accurately simulate clot deflection and penetration of stent wires into the clot, the relative movement of the clot and stent during extraction, and clot fragmentation/embolus formation. In this study, we demonstrated that coupling FEA and SPH techniques could realistically model stent retriever thrombectomy.

Background Genetic variants in apolipoprotein L1 (APOL1), a protein that protects humans from infection with African trypanosomes, explain a substantial proportion of the excess risk of chronic kidney disease affecting individuals with sub-Saharan ancestry. The mechanisms by which risk variants damage kidney cells remain incompletely understood. In preclinical models, APOL1 expressed in podocytes can lead to significant kidney injury. In humans, studies in kidney transplant suggest that the effects of APOL1 variants are predominantly driven by donor genotype. Less attention has been paid to a possible role for circulating APOL1 in kidney injury. Methods Using liquid chromatography-tandem mass spectrometry, the concentrations of APOL1 were measured in plasma and urine from participants in the Seattle Kidney Study. Asymmetric flow field-flow fractionation was used to evaluate the size of APOL1-containing lipoprotein particles in plasma. Transgenic mice that express wild-type or risk variant APOL1 from an albumin promoter were treated to cause kidney injury and evaluated for renal disease and pathology. Results In human participants, urine concentrations of APOL1 were correlated with plasma concentrations and reduced kidney function. Risk variant APOL1 was enriched in larger particles. In mice, circulating risk variant APOL1-G1 promoted kidney damage and reduced podocyte density without renal expression of APOL1. Conclusions These results suggest that plasma APOL1 is dynamic and contributes to the progression of kidney disease in humans, which may have implications for treatment of APOL1-associated kidney disease and for kidney transplantation.

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