Tumor Necrosis Factor-Alpha Blockade Ameliorates Diabetic Nephropathy In Rats

Background: Tubular injury plays a critical role in the development of diabetic nephropathy (DN), but current DN therapies do not combat tubular injury. This study was conducted to investigate if tumor necrosis factor (TNF)-alpha inhibition protects against tubular injury in diabetic rats and to examine the associated mechanisms.Methods: Kidney biopsy tissues were collected and analyzed from 12 patients with DN and 5 control subjects. Streptozotocin (STZ)-induced diabetic rats were treated with a TNF-alpha inhibitor for 12 weeks. Renal function, albuminuria, histological injury, renal TNF-alpha messenger RNA (mRNA) and the NOD- (nucleotide-binding), LRR- (domain-like receptor) and pyrin domain-containing protein 3 (NLRP3) inflammasome were assessed.Results: Diabetic patients with tubulointerstitial injury (TIN) presented with higher renal tubular expression of TNF-alpha mRNA and the NLRP3 inflammasome (P<0.05). TNF-alpha inhibition reduced albuminuria, glomerular injury and tubular injury in STZ-induced diabetic rats (P<0.05). Importantly, TNF-alpha inhibition significantly reduced the NLRP3 inflammasome in tubules (P<0.05). Moreover, TNF-alpha inhibition decreased expression of tubular interleukin (IL)-6 and IL-17A mRNA.Conclusions: TNF-alpha inhibition protects against TIN by suppressing the NLRP3 inflammasome in DN rats. Future studies may focus on the clinical protective effects of TNF-alpha inhibition using prospective observation.