Abstract
ObjectiveDiabetic nephropathy (DN) is characterized by glomerular and tubulointerstitial injury, proteinuria and remodeling. Here we examined whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses renal injury in a pre-clinical model of early DN more effectively than valsartan monotherapy.MethodsSixty-four male Zucker Obese rats (ZO) at 16 weeks of age were distributed into 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val) (68 mg kg−1 day−1; ZOSV); and Group 3: valsartan (val) (31 mg kg−1 day−1; ZOV). Group 4 received hydralazine, an anti-hypertensive drug (30 mg kg−1 day−1, ZOH). Six Zucker Lean (ZL) rats received saline (Group 5) and served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage.ResultsMean arterial pressure (MAP) increased in ZOC (+ 28%), but not in ZOSV (− 4.2%), ZOV (− 3.9%) or ZOH (− 3.7%), during the 10 week-study period. ZOC were mildly hyperglycemic, hyperinsulinemic and hypercholesterolemic. ZOC exhibited proteinuria, hyperfiltration, elevated renal resistivity index (RRI), glomerular mesangial expansion and podocyte foot process flattening and effacement, reduced nephrin and podocin expression, tubulointerstitial and periarterial fibrosis, increased NOX2, NOX4 and AT1R expression, glomerular and tubular nitroso-oxidative stress, with associated increases in urinary markers of tubular injury. None of the drugs reduced fasting glucose or HbA1c. Hypercholesterolemia was reduced in ZOSV (− 43%) and ZOV (− 34%) (p < 0.05), but not in ZOH (− 13%) (ZOSV > ZOV > ZOH). Proteinuria was ameliorated in ZOSV (− 47%; p < 0.05) and ZOV (− 30%; p > 0.05), but was exacerbated in ZOH (+ 28%; p > 0.05) (ZOSV > ZOV > ZOH). Compared to ZOC, hyperfiltration was improved in ZOSV (p < 0.05 vs ZOC), but not in ZOV or ZOH. None of the drugs improved RRI. Mesangial expansion was reduced by all 3 treatments (ZOV > ZOSV > ZOH). Importantly, sac/val was more effective in improving podocyte and tubular mitochondrial ultrastructure than val or hydralazine (ZOSV > ZOV > ZOH) and this was associated with increases in nephrin and podocin gene expression in ZOSV (p < 0.05), but not ZOV or ZOH. Periarterial and tubulointerstitial fibrosis and nitroso-oxidative stress were reduced in all 3 treatment groups to a similar extent. Of the eight urinary proximal tubule cell injury markers examined, five were elevated in ZOC (p < 0.05). Clusterin and KIM-1 were reduced in ZOSV (p < 0.05), clusterin alone was reduced in ZOV and no markers were reduced in ZOH (ZOSV > ZOV > ZOH).ConclusionsCompared to val monotherapy, sac/val was more effective in reducing proteinuria, renal ultrastructure and tubular injury in a clinically relevant animal model of early DN. More importantly, these renoprotective effects were independent of improvements in blood pressure, glycemia and nitroso-oxidative stress. These novel findings warrant future clinical investigations designed to test whether sac/val may offer renoprotection in the setting of DN.
Highlights
The impact of obesity and diabetes on kidney function and structure is well recognized due to increased incidences of diabetes-associated chronic kidney disease (CKD) and end stage renal disease (ESRD) [1,2,3]
Compared to val monotherapy, sac/val was more effective in reducing proteinuria, renal ultrastructure and tubular injury in a clinically relevant animal model of early Diabetic nephropathy (DN)
Plasma biochemical parameters and glycemic control Compared to ZL rats served as lean controls (ZLC), ZOC exhibited increased body weight, epididymal and retroperitoneal fat pad masses, fasting glucose, fasting insulin and insulin resistance (p < 0.05) (Table 1)
Summary
The impact of obesity and diabetes on kidney function and structure is well recognized due to increased incidences of diabetes-associated chronic kidney disease (CKD) and end stage renal disease (ESRD) [1,2,3]. The standard of care for the management of kidney injury involves administration of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II (Ang-II) type 1 receptor (AT1R) blockers (ARB) [6,7,8,9]. Natriuretic peptides (NP) are well known to induce cGMP synthesis that promotes natriuresis, diuresis and vasodilation and have been shown to inhibit mesangial cell proliferation and kidney fibrosis [12,13,14,15]. Earlier attempts to reduce the degradation of NPs utilizing an inhibitor of neprilysin alone (NEPi) fell short due to an increase in Ang-II levels that promote sodium retention, vasoconstriction and cardiac fibrosis [11]. NEPi were combined with ACEi; their combination increased the risk of angioedema due to inhibition of bradykinin degradation, precluding its clinical utility [11]
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