LC-MS-based metabolomics analysis to identify meprin-β-associated changes in kidney tissue from mice with STZ-induced type 1 diabetes and diabetic kidney injury

Abstract

Meprin metalloproteases have been implicated in the pathophysiology of diabetic kidney disease (DKD). Single-nucleotide polymorphisms in the meprin-β gene have been associated with DKD in Pima Indians, a Native American ethnic group with an extremely high prevalence of DKD. In African American men with diabetes, urinary meprin excretion positively correlated with the severity of kidney injury. In mice, meprin activity decreased at the onset of diabetic kidney injury. Several studies have identified meprin targets in the kidney. However, it is not known how proteolytic processing of the targets by meprins impacts the metabolite milieu in kidneys. In the present study, global metabolomics analysis identified differentiating metabolites in kidney tissues from wild-type and meprin-β knockout mice with streptozotocin (STZ)-induced type 1 diabetes. Kidney tissues were harvested at 8 wk post-STZ and analyzed by hydrophilic interaction liquid chromatography ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Principal component analysis identified >200 peaks associated with diabetes. Meprin expression-associated metabolites with strong variable importance of projection scores were indoxyl sulfate, N-γ-l-glutamyl-l-aspartic acid, N-methyl-4-pyridone-3-carboxamide, inosine, and cis-5-decenedioic acid. N-methyl-4-pyridone-3-carboxamide has been previously implicated in kidney injury, and its isomers, 4-PY and 2-PY, are markers of peroxisome proliferation and inflammation that correlate with creatinine clearance and glucose tolerance. Meprin deficiency-associated differentiating metabolites with high variable importance of projection scores were cortisol, hydroxymethoxyphenylcarboxylic acid- O-sulfate, and isovaleryalanine. The data suggest that meprin-β activity enhances diabetic kidney injury in part by altering the metabolite balance in kidneys, favoring high levels of uremic toxins such as indoxyl sulfate and N-methyl-pyridone-carboxamide.

Traditional Chinese medicine improved diabetic kidney disease through targeting gut microbiota

“…Meprin-β was found to improve diabetic kidney injury, promoting the production of uremic toxins (IS, N-methyl-pyridone-carboxamide) and altering the metabolite balance in the kidney (Gooding et al. 2019 ). A preliminary study indicated that the accumulation of IS was associated with increased kidney damage (Ellis et al.…”

Quantitative structural assessments of potential meprin β inhibitors by non-linear QSAR approaches and validation by binding mode of interaction analysis

“…9,10 Because of targeting a wide variety of substrates, meprin b influences various diverse biological processes 9,10 such as maintenance of the human granulocyte IL-6R pathways, 13 collagen deposition in the skin, 14 lung fibrosis, 15 trans-endothelial cellular migration, 16 TREM-2-mediated regulation of macrophage phagocytic potential, 17 neurotoxic amyloid b (Ab) levels, 18 mucus regulation via MUC-2, 19 as well as inflammation mechanisms. 20,21 Consequently, meprin b also contributes to several pathological conditions and diseases such as inflammation, 9,10,20,21 fibrosis, 9,10 neurodegenerative diseases like Alzheimer's disease (AD), 9,10,18 hyperkeratosis, 22 glomerulonephritis, 23 diabetic kidney injury 24 as well as inflammatory bowel diseases 25 and cancer. 9,10 However, surprisingly, no potential inhibitors have been marketed to date despite such a huge role of meprin b in several diseases.…”

The Biochemical Pathways of Nicotinamide-Derived Pyridones

“…As waste products, these by-products of NAD(P)(H) metabolism associate with aging and nephrotic dysfunction as their levels associate with advanced kidney injuries (AKI) and kidney failure [ 4 , 6 , 10 , 11 , 12 ]. Liquid chromatography combined with mass spectrometry is the most common method used to detect nicotinamide-derived pyridones in biological samples [ 13 , 14 , 15 ].…”

“…N-Methyl-2-pyridone-3-carboxamide (Me-2PY) and 2-pyridone-3-carboxamide riboside (2PYR) are the least prominent pyridones in the literature, as they are much less often detected in biological samples [9]. As waste products, these by-products of NAD(P)(H) metabolism associate with aging and nephrotic dysfunction as their levels associate with advanced kidney injuries (AKI) and kidney failure [4,6,[10][11][12]. Liquid chromatography combined with mass spectrometry is the most common method used to detect nicotinamide-derived pyridones in biological samples [13][14][15].…”

“…Possessing a systematic, reliable account of the pyridones' distribution would greatly help identify whether these species are pathophysiologically significant. As waste products, these by-products of NAD(P)(H) metabolism associate with aging and nephrotic dysfunction as their levels associate with advanced kidney injuries (AKI) and kidney failure [4,6,[10][11][12]. Liquid chromatography combined with mass spectrometry is the most common method used to detect nicotinamide-derived pyridones in biological samples [13][14][15].…”