Refinement of the HIVAN1 Susceptibility Locus on Chr. 3A1-A3 via Generation of Sub-Congenic Strains

HIV-1 transgenic mice on the FVB/NJ background (TgFVB) represent a validated model of HIV-associated nephropathy (HIVAN). A major susceptibility locus, HIVAN1, was previously mapped to chromosome 3A1-A3 in a cross between TgFVB and CAST/EiJ (CAST) strains, and introgression of a 51.9 Mb segment encompassing HIVAN1 from CAST into TgFVB resulted in accelerated development of nephropathy. We generated three sub-congenic strains carrying CAST alleles in the proximal or distal regions of the HIVAN1 locus (Sub-II, 3.02–38.93 Mb; Sub-III, 38.45–55.1 Mb and Sub-IV, 47.7–55.1 Mb, build 38). At 5–10 weeks of age, histologic injury and proteinuria did not differ between HIV-1 transgenic Sub-II and TgFVB mice. In contrast, HIV-1 transgenic Sub-III and Sub-IV mice displayed up to 4.4 fold more histopathologic injury and 6-fold more albuminuria compared to TgFVB mice, similar in severity to the full-length congenic mice. The Sub-IV segment defines a maximal 7.4 Mb interval for HIVAN1, and encodes 31 protein coding genes: 15 genes have missense variants differentiating CAST from FVB, and 14 genes show differential renal expression. Of these, Frem1, Foxo1, and Setd7 have been implicated in the pathogenesis of nephropathy. HIVAN1 congenic kidneys are histologically normal without the HIV-1 transgene, yet their global transcriptome is enriched for molecular signatures of apoptosis, adenoviral infection, as well as genes repressed by histone H3 lysine 27 trimethylation, a histone modification associated with HIV-1 life cycle. These data refine HIVAN1to 7.4 Mb and identify latent molecular derangements that may predispose to nephropathy upon exposure to HIV-1

Expression of HIV transgene aggravates kidney injury in diabetic mice

With the widespread use of combination antiretroviral agents, the incidence of HIV-associated nephropathy has decreased. Currently, HIV-infected patients live much longer and often suffer from comorbidities such as diabetes mellitus. Recent epidemiological studies suggest that concurrent HIV infection and diabetes mellitus may have a synergistic effect on the incidence of chronic kidney disease. To address this, we determined whether HIV-1 transgene expression accelerates diabetic kidney injury using a diabetic HIV-1 transgenic (Tg26) murine model. Diabetes was initially induced with low-dose streptozotocin in both Tg26 and wild-type mice on a C57BL/6 background, which is resistant to classic HIV-associated nephropathy. Although diabetic nephropathy is minimally observed on the C57BL/6 background, diabetic Tg26 mice exhibited a significant increase in glomerular injury compared with nondiabetic Tg26 mice and diabetic wild-type mice. Validation of microarray gene expression analysis from isolated glomeruli showed a significant upregulation of proinflammatory pathways in diabetic Tg26 mice. Thus, our study found that expression of HIV-1 genes aggravates diabetic kidney disease

LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts

Leucine-rich repeat kinase 2 (LRRK2) has been linked to several clinical disorders including Parkinson’s disease (PD), Crohn’s disease, and leprosy. Furthermore in rodents, LRRK2 deficiency or inhibition leads to lysosomal pathology in kidney and lung. Here we provide evidence that LRRK2 functions together with a second PD-associated gene, RAB7L1, within an evolutionarily conserved genetic module in diverse cellular contexts. In C. elegans neurons, orthologues of LRRK2 and RAB7L1 act coordinately in an ordered genetic pathway to regulate axonal elongation. Further genetic studies implicated the AP-3 complex, which is a known regulator of axonal morphology as well as of intracellular protein trafficking to the lysosome compartment, as a physiological downstream effector of LRRK2 and RAB7L1. Additional cell-based studies implicated LRRK2 in the AP-3 complex-related intracellular trafficking of lysosomal membrane proteins. In mice, deficiency of either RAB7L1 or LRRK2 leads to prominent age-associated lysosomal defects in kidney proximal tubule cells, in the absence of frank CNS pathology. We hypothesize that defects in this evolutionarily conserved genetic pathway underlie the diverse pathologies associated with LRRK2 in humans and in animal models

Actin depolymerizing factors cofilin1 and destrin are required for ureteric bud branching morphogenesis

Peer reviewe

Clinical Characteristics and Treatment Patterns of Children and Adults With IgA Nephropathy or IgA Vasculitis: Findings From the CureGN Study

Introduction: The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients. Methods: Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment. Results: A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P < 0.001), more frequently white (89.7% vs. 78.9%, P = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m2, P < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P < 0.001). Conclusion: This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies

A Fresh Perspective on Monoclonal Gammopathies of Renal Significance

International audienceMonoclonal gammopathies of renal significance (MGRS) encompass a remarkable variety of kidney diseases that result from intrinsic nephrotoxic properties of certain monoclonal Igs or their subunits. Effective disease-modifying treatments rely on the targeting of a malignant B-cell clone that may be demonstrable but often is quite hypothetical. Hence, convincing arguments for the genuine monoclonal character of the causative mono-isotypic Ig tissue deposits is needed for design of appropriate treatment strategies. The purpose of this article was to critically analyze distinct situations of suspected MGRS that occur in the practice of pathologists, nephrologists, hematologists, and immunologists. A particular focus of interest is the group of conditions known as proliferative glomerulonephritis with mono-isotypic immunoglobulin deposits (PGNMIDs), which illustrates the difficulties and ambiguities surrounding a definitive assignment of MGRS status