ABSTRACT
Podocyte loss is central to the progression of proteinuric kidney diseases leading to end-stage kidney disease (ESKD), requiring renal replacement therapy, such as dialysis. Despite modern tools and techniques, the 5-year mortality of some patients requiring dialysis remains at about 70% to 80%. Thus, there is a great unmet need for podocyte-specific treatments aimed at preventing podocyte loss and the ensuing development of ESKD. Here, we show that ablation of the podocyte death-promoting protein dendrin delays the onset of ESKD, thereby expanding the life span of mice lacking the adapter protein CD2AP. Ablation of dendrin delays onset and severity of proteinuria and podocyte loss. In addition, dendrin ablation ameliorates mesangial volume expansion and up-regulation of mesangial fibronectin expression, which is mediated by a podocyte-secreted factor. In conclusion, onset of ESKD and death can be markedly delayed by blocking the function of dendrin.
Subject(s)
Kidney Diseases/genetics , Kidney Failure, Chronic/genetics , Longevity/genetics , Nerve Tissue Proteins/genetics , Podocytes/pathology , Animals , Disease Progression , Fibroblasts/metabolism , Fibroblasts/pathology , Kidney Diseases/metabolism , Kidney Diseases/pathology , Kidney Failure, Chronic/metabolism , Kidney Failure, Chronic/pathology , Mice , Mice, Knockout , Nerve Tissue Proteins/metabolism , Podocytes/metabolism , Proteinuria/metabolism , Proteinuria/pathologyABSTRACT
BACKGROUND: Persistent depressive symptoms after acute coronary syndrome (ACS) are common and increase the risk of recurrent cardiac events and mortality. However, the neurobiological correlates of post-ACS depressive symptoms have not yet been studied. METHODS: Three months after ACS, 22 patients were scanned for the presence of cerebral deep white matter changes and microstructural abnormalities in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex. We used the Coffey Rating Scale of deep white matter changes and measures of fractional anisotropy derived from diffusion tensor imaging. Patients also completed the Beck Depression Inventory, and the number of cardiovascular comorbidities as well as modifiable cardiovascular risk factors were assessed. RESULTS: Controlling for cardiovascular comorbidity, depressive symptom severity at 3 months was negatively related to fractional anisotropy in the ACC (r = -0.72, p < 0.001), but this association disappeared when controlling for cardiovascular risk factors (p = 0.21). In comparison to patients who were non-depressed at 3 months after hospitalization (n = 14), patients with persistent depressive symptoms (n = 8) exhibited more advanced deep white matter changes overall (p < 0.02), but not when controlling for cardiovascular comorbidity. Persistently depressed patients also had lower fractional anisotropy in the ACC (p < 0.05), but this effect disappeared when controlling for modifiable cardiovascular risk factors. CONCLUSIONS: This study provides the first evidence that persistent depressive symptoms after ACS are associated with vascular brain changes. Longitudinal studies are needed to determine whether depressive symptoms precede these changes or vice versa.