Sacubitril/Valsartan Improves Progression of Early Diabetic Nephropathy in Rats Through Inhibition of NLRP3 Inflammasome Pathway

Abstract

Purpose

Diabetic nephropathy (DN), a global disease, is the leading cause of end-stage renal disease. There is a lack of specific treatment for this disease, and early intervention in disease progression is essential. In this paper, we used a rat model of early diabetic nephropathy to explore the therapeutic mechanism of sacubitril/valsartan in rats with early diabetic nephropathy.

Materials and Methods

Rats were grouped into 1 normal group; 2. Model group (DN group): STZ (45 mg/kg/d) induced early diabetic nephropathy rats; 3. Sac group: DN rats + Sac group (orally, 60 mg/kg/d) for 6 weeks. After 6 weeks, the levels of serum albumin (ALB), glucose (GLU), creatinine (Cr), urea nitrogen (BUN) and 24-h urinary protein excretion were measured. In renal tissue homogenates, NLRP3 inflammasome, proinflammatory factors IL1-β and TNF-α, oxidative stress MDA and pro-fibrotic cytokine TGF-β1 were performed. Histological analysis of kidneys by hematoxylin and eosin (HE), PAS and Masson trichrome staining.

Results

1. Sacubitril/valsartan (Sac) significantly improved renal hypertrophy, proteinuria and serum albumin levels in rats with early diabetic nephropathy (P < 0.001), and decreased GLU, Scr (P<0.001), and BUN levels (P < 0.01).2. Light microscopy of renal tissues showed glomerular hypertrophy and interstitial inflammatory cell infiltration, and mean glomerular area (MGA) and mean glomerular volume (MGV) were crucially increased in early diabetic nephropathy (P < 0.001), and the Sac group showed reduced renal pathology and improved MGA and MGV (P < 0.001).3. Kidney tissue homogenate levels of NLRP3, Caspase-1, IL1-β, TNF-α, MDA and TGF-β1 were critically, increased in DN rats (P < 0.001), and SOD was significantly decreased. All these indicators above were improved after treatment (P < 0.0001).

Conclusion

Nlrp3-inflammasome promote progression of diabetic nephropathy through inflammation, fibrosis and oxidative stress; sacubitril/valsartan ameliorated early diabetes-induced renal damage by inhibiting NLRP3 pathway activation.

Keywords:

• diabetic nephropathy
• Nlrp3-inflammasome
• sacubitril/valsartan
• oxidative stress
• inflammation
• fibrosis

Data Sharing Statement

Data supporting the results of this study are not publicly available and can be obtained from Corresponding author Yan Pan ([email protected]).

Ethics Approval and Informed Consent

The study was approved by the Ethics Committee of Bengbu Medical College (Ethics Committee No. [2020] 227) and that the experimental animals and husbandry conditions met the requirements of the Regulations on the Administration of Laboratory Animals and complied with the 3R principles of Laboratory Animal Welfare: Reduction, Substitution, Optimization.

Consent for Publication

All authors agree to the publication of this paper.

Acknowledgment

We are deeply grateful to all participants of this study.

Disclosure

The authors have no conflicts of interest to declare.

Additional information

Funding

Natural Science Foundation of Bengbu Medical College Project (BYKY1838ZD)Key Special Project on Translational Medicine, Bengbu Medical College, (BYTM2019038).