Synergistic Effects of Leflunomide and Benazepril in Streptozotocin-Induced Diabetic Nephropathy

Jin, Hua; Piao, Shang Guo; Jin, Ji Zhe; Ying, Jianming; Cui, Zhen Hua; Jin, Hai Feng; Zheng, Hongliang; Li, Jin Ji; Jiang, Yu; Yang, Chul Woo; Li, Can

doi:10.1159/000362556

Cited by 15 publications

(12 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been confirmed that angiotensin converting enzyme inhibitor (ACEI) drugs can lower blood pressure and reduce significant proteinuria, protecting the kidneys and delaying the progression of kidney disease (32). Clinically, benazepril, a type of ACEI, is important in ameliorating diabetic kidney damage (33). In the present study, benazepril treatment was used as a positive control, and the results showed that tacrolimus and benazepril significantly reduced the levels of urinary protein, Scr and BUN in groups F and L, compared with those in group DN (P<0.05).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of tacrolimus on podocytes in early diabetic nephropathy in rats

Peng

Chang

Wang

et al. 2017

Molecular Medicine Reports

View full text Add to dashboard Cite

The aim of the present study was to investigate the protective effect of tacrolimus on early podocyte damage in rats with diabetic nephropathy (DN). A total of 38 normal male Sprague‑Dawley rats were randomly divided into four groups: Normal control group (group N; n=8), DN group (n=10), tacrolimus (FK506) treatment group (group F; n=10), benazepril (Lotensin) treatment group (group L; n=10). The rats in groups DN, F and L were administered with streptozotocin (STZ; 60 mg/kg) by intraperitoneal injection to establish the diabetic rat model. After 4 weeks, the diabetic rat model was established, and rats in the different groups were administered intragrastically with the respective drugs. Blood glucose (BS), body weight (BW) and 24‑h urine protein were detected every 4 weeks, serum creatinine (SCr), blood urea nitrogen (BUN) and kidney weight/body weight (KW/BW) were measured at the end of the 8 weeks of drug treatment. Renal pathological changes were observed under a light microscope and electron microscope. Expression of nephrin, which is a podocyte‑specific marker, was detected using western blot analysis. The results showed that the levels of SCr, BUN, KW/BW and 24‑h urine protein in groups D, F and L were significantly higher, compared with those in group N (P<0.05). No significant differences were found between groups F and L for the above indicators, with the exception of BS. However, all indices were significantly lower, compared with those in group DN (P<0.05). Renal pathological expression was normal in group N under light microscopy. There were significant increases in the glomerular volume, proliferative mesangial cells, width of the mesangial area and thickness of the basement membrane in group DN, however, all the above pathological characteristics were reduced in groups F and L, compared with group DN (P<0.05). No significant difference was found between groups F and L. A widened glomerular basement membrane, and disorder, widening and fusion of podocyte processes were observed under the electron microscope in group DN, however, these were reduced in groups F and L, compared with group DN (P<0.05). The results of the western blot analysis showed that the expression of nephrin decreased by 60.1% in group DN, compared with group N, and significant recovery in the expression of nephrin was observed in groups F and L (P<0.05). Tacrolimus reduced urinary protein and slowed the progression of DN, partially by recovering the protein expression of nephrin in the renal tissue of diabetic rats, and maintaining the integrity of the structure and function of podocytes.

show abstract

Section: Discussionmentioning

confidence: 99%

Protective effects of tacrolimus on podocytes in early diabetic nephropathy in rats

Peng

Chang

Wang

et al. 2017

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…In particular, the expression of TLR2 and TLR4 was enhanced in STZ-induced rat models of diabetes mellitus 164,165 and global deletion of Tlr4 in mice resulted in decreased renal inflammation and fibrosis associated with the reduction in the expression of MCP-1 147 .…”

Section: [H2] Influence Of Chemokinesmentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

View full text Add to dashboard Cite

Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

show abstract

“…As a result, chronic TAC nephropathy involves both renal dysfunction and proteinuria [3]. It is well known that TGF-β1 plays a pivotal role in renal scarring in a wide range of kidney diseases probably by its action on ECM synthesis and degradation [25-27]. It has been confirmed by in vivo and in vitro studies that TAC induces TGF-β1 expression either directly or indirectly.…”

Section: Discussionmentioning

confidence: 99%