A Hyaluronan Synthesis Inhibitor Delays the Progression of Diabetic Kidney Disease in A Mouse Experimental Model

Abstract

Background: The role of hyaluronan (HA) in the development and progression of diabetic kidney disease (DKD), as well as the precise mechanisms and consequences of HA involvement in this pathology are still to be clarified. Methods: In this study, we assayed the effects of the HA synthesis inhibitor 4-methylumbelliferone (4-MU) on the development of DKD. Diabetic type 2 model mice (eNOS-/- C57BLKS/Jdb) were fed artificial diets containing 5% 4-MU or not for 9 weeks. Plasma glucose, glomerular filtration rate (GFR), albumin to creatinine ratio (ACR), and biomarkers of kidney function and systemic inflammation were measured at baseline and after treatment. Diabetic nephropathy was further characterized in treated and control mice by histopathology. Results: Treated animals consumed a daily dose of approximately 6.2 g of 4-MU per kg of body weight. At the end of the experimental period, the 4-MU supplemented diet resulted in a significant decrease in non-fasting plasma glucose (516 [interquartile range 378-1170] vs. 1149 [875.8-1287] mg/dL, P=0.050) and a trend toward lower HA kidney content (5.6 ± 1.5 vs. 8.8 ± 3.1 ng/mg of kidney weight, P=0.070) compared to the control diet, respectively. Diabetic animals treated with 4-MU showed significantly higher GFR and lower urine ACR and plasma cystatin C levels than diabetic controls. Independent histological assessment of DKD also demonstrated a significant decrease in mesangial expansion score and glomerular injury index in 4-MU-treated mice compared to controls. Plasma glucose showed a strong correlation with kidney HA levels (r=0.66, P=0.0098). Both total hyaluronan (r=0.76, P=0.0071) and low-molecular-weight hyaluronan content (r=0.64, P=0.036) in the kidneys correlated with urine ACR in mice. Conclusion: These results show that the hyaluronan synthesis inhibitor 4-MU effectively slowed the progression of DKD and constitutes a potential new therapeutic approach to treat DKD.

Hyaluronan Inhibition as a Therapeutic Target for Diabetic Kidney Disease: What Is Next?

“…42,46 Our study has shown the benefits of 4-MU, a HA synthesis inhibitor, in slowing DKD progression in animal experimental models with potential important benefit in glucose control. 3 Phase 1 study on 4-MU among healthy human adults has been completed and published, highlighting its safety and tolerabiltiy. 59 On the basis of all of this in addition to the results of other in-human published studies, we believe that it is time for a phase 2 in-human study to evaluate the safety and efficacy of using 4-MU among patients with DKD.…”

“… 40 , 41 This increased renal HA accumulation has been linked to worsened proteinuria, faster loss of kidney function, and increased cardiovascular events. 3 , 41 , 42 Afferent and efferent AH is one of the key pathologic findings in DKD. 5 There have been various pathologic classifications of AH on the basis of the number of arterioles affected, such as the criteria proposed by Tervaert et al , 43 or the wall thickness and percentage of luminal area occlusions in the most severely affected arteriole 44 or the number of arterioles affected and the circumferences of the arterioles involved, as in the Banff lesion score.…”

“…We have conducted a study to assay the effects of the HA synthesis inhibitor, 4-MU, on the progression of DKD. 3 We used the eNOS −/− C57BLKS/J db mouse model for these experiments. The double homozygous mouse develops type 2 DM and becomes moderately hypertensive.…”

“…Histopathology analysis showed significantly higher glomerular injury index and mesangial expansion in the diabetic control group when compared with the 4-MU–treated group (Table 1 taken from ref. 3 with permission). Both diabetic groups had higher HA kidney content when compared with their nondiabetic siblings, highlighting the pathologic HA deposits as a complication of DM.…”

“…Both total HA and LMW HA levels in kidneys strongly correlated with urine ACR (Figure 4 taken from ref. 3 with permission). Importantly, there were no signs of severe AH, tubulitis, or nephritis in the 4-MU–treated group (Table 1 taken from ref.…”