Punicalagin Protects Diabetic Nephropathy by Inhibiting Pyroptosis Based on TXNIP/NLRP3 Pathway

Abstract

Diabetic nephropathy is a diabetic complication caused by chronic inflammation. As the primary polyphenol in pomegranate, punicalagin is believed to have significant anti-inflammatory properties. In this study, we established a mice model for diabetes induced by high-fat diet (HFD)/ streptozotocin (STZ) to verify the protective effect of punicalagin in vivo. The results show that the blood urea nitrogen (BUN), serum creatinine (CREA), and the urine albumin to creatinine ratio (UACR) were significantly decreased in diabetic mice after punicalagin intervention, and the symptoms of glomerular interstitial hyperplasia and glomerular hypertrophy were alleviated. Pyroptosis is an essential manner of programmed cell death in the inflammatory response; the expression of pyroptosis-related proteins such as interleukin-1 (IL-1β), cysteinyl aspartate-specific protease-1 (caspase-1), gasdermin D (GSDMD), and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) was decreased in our study, which proved that the administration of punicalagin for eight weeks can significantly inhibit pyroptosis in mice. In addition, punicalagin reduced high glucose-mediated protein expressions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and alleviated mitochondria damage. Low expression of NOX4 inhibits the dissociation of thioredoxin (Trx) and thioredoxin-interacting protein (TXNIP) and the suppression of NLRP3 inflammasome activation. To summarize, our study provided evidence that punicalagin can alleviate diabetic nephropathy, and the effect is associated with downregulating the expression of NOX4, inhibiting TXNIP/NLRP3 pathway-mediated pyroptosis, suggesting its therapeutic implications for complications of diabetes.

Role of Pyroptosis in Diabetes and Its Therapeutic Implications

“…The Western blotting analysis has confirmed that PU administration can tremendously inhibit NLRP3, GSDMD, and caspase-1 expression levels in diabetic mice models. 125 Recent research has reported that caspase-1 blocker YVAD or NLRP3 blocker glyburide can significantly suppress GSDMD, NLRP3, caspase-1 protein expression levels in retinal pericytes. 184 Notably, the silencing of GSDMD can also inhibit HG-induced retinal pericytes.…”

Relevance of the Pyroptosis-Related Inflammasome Pathway in the Pathogenesis of Diabetic Kidney Disease

“…An et al. ( 110 ) administered punicalagin to a mouse model of DN induced by a high-fat diet (HFD) and STZ. After punicalagin intervention, blood urea nitrogen (BUN), serum creatinine (CREA), and urine albumin-creatinine ratios (UACR) were significantly reduced, and the glomerular interstitial hyperplasia and glomerular hypertrophy scores were reduced.…”

The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target

“…Conversely, TXNIP has a pro-inflammatory role leading to cardiac, vascular and endothelial dysfunctions [ 13 , 19 , 21 , 66 , 67 , 68 , 143 , 144 ]. Numerous studies conducted since the 2000s suggest that TXNIP may bind to the NLRP3 inflammasome, which enhances the inflammatory response, as reviewed almost a decade ago [ 65 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ] and summarized in Figure 1 . TXNIP and NLRP3 physically interact to activate the inflammasome [ 83 ].…”

“…TXNIP is also overexpressed in the context of diabetes. Data from the literature identify TXNIP as a potential target in diabetes complications such as diabetic retinopathy, nephropathy, cardiomyopathy, and impaired post-ischemic revascularization [ 59 , 67 , 79 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 ]. In a rat model of diabetic cardiomyopathy, TXNIP deletion in cardiomyocytes induces an improved inotropic response to β-adrenergic stimulation [ 144 ].…”