The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN) response signatures in tubular cells and in keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous, and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histological differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

Abstract-In ventricular cardiac myocytes, T-tubule density is an important determinant of the synchrony of sarcoplasmic reticulum (SR) Ca 2ϩ release and could be involved in the reduced SR Ca 2ϩ release in ischemic cardiomyopathy. We therefore investigated T-tubule density and properties of SR Ca 2ϩ release in pigs, 6 weeks after inducing severe stenosis of the circumflex coronary artery (91Ϯ3%, Nϭ13) with myocardial infarction (8.8Ϯ2.0% of total left ventricular mass). Severe dysfunction in the infarct and adjacent myocardium was documented by magnetic resonance and Doppler myocardial velocity imaging. Myocytes isolated from the adjacent myocardium were compared with myocytes from the same region in weight-matched control pigs. T-tubule density quantified from the di-8-ANEPPS (di-8-butyl-aminonaphthyl-ethylene-pyridinium-propyl-sulfonate) sarcolemmal staining was decreased by 27Ϯ7% (PϽ0.05). Synchrony of SR Ca 2ϩ release (confocal line scan images during whole-cell voltage clamp) was reduced in myocardium myocytes. Delayed release (ie, ] i occurring later than 20 ms) occurred at 35.5Ϯ6.4% of the scan line in myocardial infarction versus 22.7Ϯ2.5% in control pigs (PϽ0.05), prolonging the time to peak of the line-averaged [Ca 2ϩ ] i transient (121Ϯ9 versus 102Ϯ5 ms in control pigs, PϽ0.05). Delayed release colocalized with regions of T-tubule rarefaction and could not be suppressed by activation of protein kinase A. The whole-cell averaged [Ca 2ϩ ] i transient amplitude was reduced, whereas L-type Ca 2ϩ current density was unchanged and SR content was increased, indicating a reduction in the gain of Ca 2ϩ -induced Ca 2ϩ release. In conclusion, reduced T-tubule density during ischemic remodeling is associated with reduced synchrony of Ca 2ϩ release and reduced efficiency of coupling Ca 2ϩ influx to Ca Key Words: myocardial infarction Ⅲ contractility Ⅲ myocytes Ⅲ calcium A lthough new therapeutic approaches have decreased the mortality associated with myocardial infarction (MI) over the past decades, 1 many patients nevertheless sustain a regional loss of myocardial contractile tissue following an ischemic event. The resulting increased hemodynamic burden on the left ventricle leads to structural and functional changes in the remaining viable myocardium, which further reduces ventricular performance, a process referred to as myocardial remodeling. 2 Sustained regional chronic and/or intermittent ischemia further contributes to this process, and the resulting ischemic cardiomyopathy is currently among the major causes of heart failure. 3 Contractile dysfunction of the ventricle is partly related to the abnormal loading in vivo 4 and partly to the intrinsic properties of the cardiomyocytes. Myocytes isolated from patients with ischemic cardiomyopathy at the time of heart transplantation have a reduced contractile function resulting from abnormal Ca 2ϩ handling. [5][6][7] Animal models have examined the mechanisms of cellular dysfunction in ischemic cardiomyopathy in more detail. Myocytes from the infarct border...