Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN pathogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the GBM. Loss of GBM HS in diabetic kidney was associated with increased glomerular expression of heparanase; however, the causal involvement of heparanase in the pathogenesis of DN has not been demonstrated. We report for the first time the essential involvement of heparanase in DN. With the use of Hpse-KO mice, we found that deletion of the heparanase gene protects diabetic mice from DN. Furthermore, by investigating the molecular mechanism underlying induction of the enzyme in DN, we found that transcription factor early growth response 1 (Egr1) is responsible for activation of heparanase promoter under diabetic conditions. The specific heparanase inhibitor SST0001 markedly decreased the extent of albuminuria and renal damage in mouse models of DN. Our results collectively underscore the crucial role of heparanase in the pathogenesis of DN and its potential as a highly relevant target for therapeutic interventions in patients with DN.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is closely associated with colon cancer. Expression of the enzyme heparanase is clearly linked to colon carcinoma progression, but its role in UC is unknown. Here we demonstrate for what we believe to be the first time the importance of heparanase in sustaining the immune-epithelial crosstalk underlying colitis-associated tumorigenesis. Using histological specimens from UC patients and a mouse model of dextran sodium sulfate–induced colitis, we found that heparanase was constantly overexpressed and activated throughout the disease. We demonstrate, using heparanase-overexpressing transgenic mice, that heparanase overexpression markedly increased the incidence and severity of colitis-associated colonic tumors. We found that highly coordinated interactions between the epithelial compartment (contributing heparanase) and mucosal macrophages preserved chronic inflammatory conditions and created a tumor-promoting microenvironment characterized by enhanced NF-κB signaling and induction of STAT3. Our results indicate that heparanase generates a vicious cycle that powers colitis and the associated tumorigenesis: heparanase, acting synergistically with the intestinal flora, stimulates macrophage activation, while macrophages induce production (via TNF-α–dependent mechanisms) and activation (via secretion of cathepsin L) of heparanase contributed by the colon epithelium. Thus, disruption of the heparanase-driven chronic inflammatory circuit is highly relevant to the design of therapeutic interventions in colitis and the associated cancer.

Purpose: Treatment options for unresectable Paraganglioma (PGL)/Phaeochromocytoma (PCC), especially with uncontrolled secondary hypertension (HTN) are limited. Preliminary studies with PRRT suggest efficacy but data on HTN control and survival are lacking. We assessed PRRT outcomes in such patients from 2 referral centres. Methods: 20 consecutive patients (M:F=13:7; 21-77y.o.) with high somatostatin receptor (SSTR) expression treated with ¹⁷⁷Lu-DOTA-octreotate, 9 with radiosensitising chemotherapy, were retrospectively reviewed. Median cumulative activity was 22 GBq (1-4 cycles, median 4). Fourteen patients were treated for uncontrolled HTN, and 6 for progressive or symptomatic metastatic disease or local recurrence. Results: Three months post-PRRT, 8/14 patients treated for HTN required reduced medication doses, 5 patients had no change in anti-HTN doses, and 1 patient was lost to follow-up. 86% had serum chromogranin-A reduction. For the entire cohort, 36% had disease regression (29% partial, 7% minor response) on CT, with stable findings in 50%. Three other patients had bony disease evaluable only on SSTR imaging (2 partial response, 1 stable). Median progression-free survival was 39 months, median overall survival was not reached (5 deaths, median follow-up 28 months). Four patients had Grade 3 lymphopenia, 2 Grade 3 thrombocytopenia. Renal impairment in 2 patients was attributed to underlying disease processes. Conclusions: Our results indicate that PRRT achieves worthwhile clinical and biochemical responses with low toxicity as well as controlling secondary HTN in most patients with PCC/PGL and encouraging survival. PRRT also has potential logistic and radiation-safety advantages over conventional ¹³¹I-MIBG therapy and warrants prospective evaluation in this clinically heterogeneous disease.