Prebiotic prevents impaired kidney and renal Oat3 functions in obese rats

Abstract

Obesity is health issue worldwide, which can lead to kidney dysfunction. Prebiotics are non-digestible foods that have beneficial effects on health. This study aimed to investigate the effects of xylooligosaccharide (XOS) on renal function, renal organic anion transporter 3 (Oat3) and the mechanisms involved. High-fat diet was provided for 12 weeks in male Wistar rats. After that, the rats were divided into normal diet (ND); normal diet treated with XOS (NDX); high-fat diet (HF) and high-fat diet treated with XOS (HFX). XOS was given daily at a dose of 1000 mg for 12 weeks. At week 24, HF rats showed a significant increase in obesity and insulin resistance associated with podocyte injury, increased microalbuminuria, decreased creatinine clearance and impaired Oat3 function. These alterations were improved by XOS supplementation. Renal MDA level and the expression of AT1R, NOX4, p67, 4-HNE, phosphorylated PKCα and ERK1/2 were significantly decreased after XOS treatment. In addition, Nrf2-Keap1 pathway, SOD2 and GCLC expression as well as renal apoptosis were also significantly reduced by XOS. These data suggest that XOS could indirectly restore renal function and Oat3 function via the reduction of oxidative stress and apoptosis through the modulating of AT1R-PKCα-NOXs activation in obese insulin-resistant rats. These attenuations were instigated by the improvement of obesity, hyperlipidemia and insulin resistance.

Dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, slows the progression of renal complications through the suppression of renal inflammation, endoplasmic reticulum stress and apoptosis in prediabetic rats

“…Activation of the apoptotic pathway in HFD‐fed rats was demonstrated by the upregulated pro‐apoptotic protein Bax and downregulated anti‐apoptotic protein Bcl‐2, with the subsequent release of cytochrome c, leading to the activation of cleaved caspase‐3. These findings, which are in agreement with previous studies, suggest a correlation between the increase in transcriptional CHOP protein and the activation of the apoptotic pathway. Alternatively, the increased expression of renal Calpain 2 and Caspase‐12 in HFD‐fed rats could also lead to ER‐calcium leak‐induced apoptosis through direct activation of Caspase‐3 .…”

“…The results described above, suggest that dapagliflozin and metformin ameliorated renal lipotoxicity and oxidative stress, which led to the alteration of anti‐oxidative enzymes in the kidney tissue. Our previous study in obese rats showed that the increased renal SOD expression was mediated by the activation of the Nrf2/Keap1 pathway . Increased oxidative stress induced the dissociation of Keap1 protein from Nrf2 and led to the translocation of Nrf2 into the nucleus, leading to the activation of the antioxidant response element and upregulation of antioxidant‐related enzyme expressions .…”

“…Giving weight to the concept that obesity is recognized as a chronic low‐grade systemic inflammatory disease with accumulation of pro‐inflammatory cytokines. It has been reported that, after the onset and progression of obesity and insulin resistance, inflammation and oxidative stress play important roles in the pathogenesis of renal injury . Interestingly, a recent study has shown the role of inflammation in kidney disease in the development of kidney lipid accumulation in obese mice.…”

Gut Microbiota-Kidney Cross-Talk in Acute Kidney Injury

“…A double-blind placebo-controlled randomized cross-over trial using synbiotics (co-administration of pre- and probiotics) showed beneficial effects on CKD stage 4–5 patients [77]. Table 1 summarizes recent advances in the use of probiotics and prebiotics as novel treatments for kidney disease [78,79][80] [81] [82] [83] [84] [85] [86].…”

Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions

“…The transporter expression and function may be modulated by certain drugs, phytomedicines, or xenobiotics, resulting in altered disposition of clinical substances, which is an indirect manner of obtaining transporter-mediated DDIs, in contrast to direct interaction with the transporter-like inhibitors or substrates [4]. For example, administration of 1α,25-dihydroxyvitamin D3, mercuric chloride, or methotrexate decreased OAT3 expression in crude or basolateral membranes of rat kidneys; while the renal expression was increased in normal rats by ochratoxin A treatment, in diabetic rats by insulin or atorvastatin plus insulin treatment, or in obese rats by prebiotic Lactobacillus paracasei HII01 or xylooligosaccharide treatment [18][19][20][21][22][23][24][25].…”