Differing sensitivities to angiotensin converting enzyme inhibition of kidney disease mediated by APOL1 high-risk variants G1 and G2.

Apolipoprotein L1 (APOL1) variants G1 and G2 contribute to the excess risk of kidney disease in individuals of recent African ancestry. Since disease mechanisms and optimal treatments remain controversial, we study the effect of current standard-of-care drugs in mouse models of APOL1 kidney disease. Experiments were performed in APOL1 BAC-transgenic mice, which develop proteinuria and glomerulosclerosis following injection with a pCpG-free IFN-γ plasmid. Proteinuric, plasmid injected G1/G1 and G2/G2 mice were randomized to drug treatment or no treatment. Lisinopril, dapagliflozin, and hydralazine were administered in drinking water starting day seven. The urine albumin/creatinine ratio was measured twice weekly, and the kidneys examined histologically with the focal segmental glomerulosclerosis score computed from periodic acid-Shiff-stained sections. The angiotensin converting enzyme inhibitor lisinopril, at standard dose, reduced proteinuria by approximately 90-fold and reduced glomerulosclerosis in the APOL1 G1/G1 BAC-transgenic mice. These effects were independent of blood pressure. Dapagliflozin did not alter disease progression in either G1/G1 or G2/G2 mice. Proteinuria reduction and glomerulosclerosis in G2/G2 BAC-transgenic mice required lisinopril doses two times higher than were effective in G1/G1 mice but achieved a much smaller benefit. Therefore, in these BAC-transgenic mouse models of APOL1 disease, the anti-proteinuric and anti-glomerulosclerotic effects of standard dose lisinopril were markedly effective in G1/G1 compared with G2/G2 APOL1 mice. Comparable reduction in blood pressure by hydralazine treatment provided no such protection. Neither G1/G1 nor G2/G2 mice showed improvement with the sodium-glucose cotransporter-2 inhibition dapagliflozin. Thus, it remains to be determined if similar differences in ACE inhibitor responsiveness are observed in patients.

A Novel Dual-Function Nitric Oxide Donor Therapy for Preeclampsia-A Proof-of-Principle Study in a Murine Model.

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy that is associated with substantial morbidity and mortality for the mother and fetus. Reduced nitric oxide bioavailability and oxidative stress contribute to the maternal and fetal pathophysiology of PE. In this study, we evaluated the efficacy of a novel dual-function nitric oxide donor/redox modulator, AKT-1005, in reducing PE symptoms in a mouse model of PE. Method: The potential therapeutic effect of AKT-1005 was tested in an animal model of Ad.sFlt-1-induced hypertension, proteinuria and glomerular endotheliosis, a model of PE. Pregnant Ad.sFlt-1-overexpressing CD1 mice were randomized into groups administered AKT-1005 (20 mg/kg) or a vehicle using a minipump on gd11 of pregnancy, and the impact on blood pressure and renal and placental damage were assessed. Results: In healthy female mice, ex vivo treatment of resistance vessels with AKT-1005 induced vasorelaxation, and 6 days of treatment in vivo did not significantly alter blood pressure with or without pregnancy. When given for 6 days during pregnancy along with Ad.sFlt-1-induced PE, AKT-1005 significantly increased plasma nitrate levels and reduced hypertension, renal endotheliosis and plasma cystatin C. In the placenta, AKT-1005 improved placental function, with reduced oxidative stress and increased endothelial angiogenesis, as measured by CD31 staining. As such, AKT-1005 treatment attenuated the Ad.sFlt-1-induced increase in placental and free plasma soluble endoglin expression. Conclusions: These data suggest that AKT-1005 significantly attenuates the sFlt-1-induced PE phenotypes by inhibiting oxidative stress, the anti-angiogenic response, and increasing NO bioavailability. Additional research is warranted to investigate the role of AKT-1005 as a novel therapeutic agent for vascular disorders such as preeclampsia.

Blocking IFNAR1 inhibits multiple myeloma-driven Treg expansion and immunosuppression.

Despite significant advances in the treatment of multiple myeloma (MM), most patients succumb to disease progression. One of the major immunosuppressive mechanisms that is believed to play a role in myeloma progression is the expansion of regulatory T cells (Tregs). In this study, we demonstrate that myeloma cells drive Treg expansion and activation by secreting type 1 interferon (IFN). Blocking IFN α and ß receptor 1 (IFNAR1) on Tregs significantly decreases both myeloma-associated Treg immunosuppressive function and myeloma progression. Using syngeneic transplantable murine myeloma models and bone marrow (BM) aspirates of MM patients, we found that Tregs were expanded and activated in the BM microenvironment at early stages of myeloma development. Selective depletion of Tregs led to a complete remission and prolonged survival in mice injected with myeloma cells. Further analysis of the interaction between myeloma cells and Tregs using gene sequencing and enrichment analysis uncovered a feedback loop, wherein myeloma-cell-secreted type 1 IFN induced proliferation and expansion of Tregs. By using IFNAR1-blocking antibody treatment and IFNAR1-knockout Tregs, we demonstrated a significant decrease in myeloma-associated Treg proliferation, which was associated with longer survival of myeloma-injected mice. Our results thus suggest that blocking type 1 IFN signaling represents a potential strategy to target immunosuppressive Treg function in MM.