Increased lysosomal proteolysis counteracts protein accumulation in the proximal tubule during focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a prevalent cause of end-stage renal disease, but the mechanisms underlying progression are unresolved. Lysosomal protein accumulation in the proximal tubule, mediated by megalin and cubilin endocytosis of increased amounts of filtered protein, is thought to result in inflammation and fibrosis. Here we determine whether release of inflammatory and fibrotic mediators in response to protein overload in the proximal tubule is caused by lysosomal enzyme deficits and insufficient proteolysis. As a model of FSGS, we used inducible podocyte-specific podocin-knockout mice analyzed at different time points. The content of megalin and cubilin ligands increased in the lysosomes after onset of proteinuria; however, protein and mRNA levels of megalin and cubilin showed only minor changes. To determine if the elevated lysosomal ligand content was caused by deficiency of enzymes, we analyzed protein and mRNA levels of lysosomal enzymes and found increased endogenous synthesis. Injection of dye-quenched fluorescent and iodinated albumin showed that proteolytic turnover in lysosomes of knockout mice adapted to the increased protein load. Inflammatory and fibrotic signals were increased early in disease, although the majority of lysosomes degraded endocytosed proteins effectively. Thus, insufficient lysosomal degradation in FSGS is not the cause of the inflammation and fibrosis during kidney disease.

Reversible and selective O2 chemisorption in a porous metal-organic host material.

The metal-organic host material [{Co(III)(2)(bpbp)(O(2))}(2)bdc](PF(6))(4) (1·2O(2); bpbp(-) = 2,6-bis(N,N-bis(2-pyridylmethyl)aminomethyl)-4-tert-butylphenolato; bdc(2-) = 1,4-benzenedicarboxylato) displays reversible chemisorptive desorption and resorption of dioxygen through conversion to the deoxygenated Co(II) form [{Co(II)(2)(bpbp)}(2)bdc](PF(6))(4) (1). Single crystal X-ray diffraction analysis indicates that the host lattice 1·2O(2), achieved through desorption of included water guests from the as-synthesized phase 1·2O(2)·3H(2)O, consists of an ionic lattice containing discrete tetranuclear complexes, between which lie void regions that allow the migration of dioxygen and other guests. Powder X-ray diffraction analyses indicate that the host material retains crystallinity through the dioxygen desorption/chemisorption processes. Dioxygen chemisorption measurements on 1 show near-stoichiometric uptake of dioxygen at 5 mbar and 25 °C, and this capacity is largely retained at temperatures above 100 °C. Gas adsorption isotherms of major atmospheric gases on both 1 and 1·2O(2) indicate the potential suitability of this material for air separation, with a O(2)/N(2) selectivity factor of 38 at 1 atm. Comparison of oxygen binding in solution and in the solid state indicates a dramatic increase in binding affinity to the complex when it is incorporated in a porous solid.