Antagonism of proNGF or its receptor p75NTR reverses remodelling and improves bladder function in a mouse model of diabetic voiding dysfunction

ALBA GALAN; SAMER SHAMOUT; LYSANNE CAMPEAU; PHILIPPE G. CAMMISOTTO; PABLO F BARCELONA; ABUBAKR H. MOSSA; MONICA VELASQUEZ FLORES; H. URI SARAGOVI

DIABETOLOGIA

SPRINGER

Lugar: Berlin; Año: 2020

0012-186X

AbstractAims/hypothesis Although 80% of diabetic patients will suffer from voiding difficulties and urinary symptoms, defined asdiabetic voiding dysfunction (DVD), therapeutic targets and treatment options are limited. We hypothesise that the blockadeof the pro-nerve growth factor (NGF)/p75 neurotrophin receptor (p75NTR) axis by an anti-proNGF monoclonal antibody or by asmall molecule p75NTR antagonist (THX-B) can restore bladder remodelling (represented by bladder weight) in an animal modelofDVD. Secondary outcomes of the study include improvements in bladder compliance, contractility and morphology, as well asin voiding behaviour, proNGF/NGF balance and TNF-α expression.Methods In a streptozotocin-induced mouse model of diabetes, diabetic mice received either a blocking anti-proNGFmonoclonal antibody or a p75NTR antagonist small molecule as weekly systemic injections for 4 weeks. Animals weretested at baseline (at 2 weeks of diabetes induction), and after 2 and 4 weeks of treatment. Outcomes measured werevoiding function with voiding spot assays and cystometry. Bladders were assessed by histological, contractility andprotein expression assays.Results Diabetic mice showed features of DVD as early as 2 weeks after diabetes diagnosis (baseline) presented by hypertrophy,reduced contractility and abnormal cystometric parameters. Following treatment initiation, a twofold increase (p < 0.05) inuntreated diabetic mouse bladder weight and thickness compared with non-diabetic controls was observed, and this changewas reversed by p75NTR antagonism (37% reduction in bladder weight compared with untreated diabetic mice [95% CI 14%,60%]) after 4 weeks of treatment. However, blocking proNGF did not help to reverse bladder hypertrophy. While diabetic micehad significantly worse cystometric parameters and contractile responses than non-diabetic controls, proNGF antagonismnormalised bladder compliance (0.007 [Q1?Q3; 0.006?0.009] vs 0.015 [Q1?Q3; 0.014?0.029] ml/cmH2O in untreated diabeticmice, representing 62% reduction [95% CI 8%, 110%], p < 0.05) and contractility to KCl, carbachol and electrical field stimulation(p < 0.05 compared with the diabetic group) after 2 weeks of treatment. These effects were not observed after 4 weeks oftreatment with proNGF antagonist. p75NTR antagonism did not show important improvements in cystometric parameters after2 weeks of treatment. Slightly improved bladder compliance (0.01 [Q1?Q3; 0.009?0.012] vs 0.013 [Q1?Q3; 0.011?0.016] ml/cmH2O for untreated diabetic mice) was seen in the p75NTR antagonist-treated group after 4 weeks of treatment with significantlystabilised contractile responses to KCl, carbachol and electric field stimulation (p < 0.05 for each) compared with diabetic mice.