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Ramulus Mori (Sangzhi) Alkaloids (SZ-A) ameliorate non-diabetic chronic kidney disease by modulating fatty acid metabolism and restoring mitochondrial homeostasis in rats

ABSTRACT: Chronic kidney disease (CKD) has emerged as a significant global public health issue due to its rising prevalence. The co-morbidity of CKD and diabetes is becoming increasingly severe, with diabetes being a primary cause of CKD leading to end-stage kidney disease (ESKD). Therefore, there is an urgent need to develop drugs that offer comprehensive benefits for patients with diabetes and CKD. This has also become a trend in the development of new hypoglycemic drugs. SZ-A is a natural drug approved by the National Medical Products Administration (NMPA) for treating type 2 diabetes mellitus. It has been shown to have good hypoglycemic effects and excellent safety. Subsequent in-depth studies have confirmed that it also has multiple pharmacological effects, including inhibiting colon inflammation, reducing body weight, alleviating non-alcoholic fatty liver disease, and improving insulin resistance. Our team's preliminary research found that SZ-A has the potential to significantly improve the progression of diabetic nephropathy and has a wide distribution in renal tissues. However, the mechanism by which SZ-A exerts its renoprotective effects has not been fully elucidated. It is unclear whether its effect on renal function is dependent on its glucose-lowering effect or if it acts directly on the kidney. The objective of this study was to evaluate the effect of SZ-A on non-diabetic chronic kidney disease by constructing an adenine-induced chronic kidney disease model. The study aimed to explore the mechanism of action of SZ-A in depth, both in vivo and ex vivo, and to elucidate the effect and mechanism of action of SZ-A and its components on renal function. The study results indicate that SZ-A can alleviate adenine-induced renal function decline in a dose-dependent manner. This therapeutic effect does not depend on the glucose-lowering effect. The SZ-A treatment group exhibited improvements in renal fibrosis, inflammation, and oxidative stress compared to the model group. Renal transcriptome analysis revealed that the protective effect of SZ-A was associated with enhanced fatty acid oxidation and decreased inflammation. Both the animal and cellular levels confirmed SZ-A's ameliorative effect on these factors, with DNJ playing a significant role. This study presents an innovative finding on the molecular mechanism through which SZ-A enhances renal function in patients with type 2 diabetes mellitus and concurrent CKD. The study reveals that SZ-A regulates energy metabolism, protects mitochondria, and identifies the single component that plays a major role. These findings provide scientific support for expanding therapeutic options and promoting the rationalization of drug use in clinical settings.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE261354 | GEO | 2024/03/14

REPOSITORIES: GEO

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Project description:Kidney stones (KS) are very common, excruciating, and are associated with tremendous healthcare cost, chronic kidney disease (CKD), and end stage renal disease (ESRD). Most KS are composed of calcium oxalate and very small increases in urine oxalate concentration increase the risk for stone formation. Besides its critical role in the pathogenesis of KS, emerging data suggest that disturbed oxalate homeostasis (hyperoxaluria and/or hyperoxalemia) contributes to CKD progression, CKD - and ESRD-associated cardiovascular diseases, progression of cyst growth in autosomal dominant polycystic kidney disease (ADPKD), and delayed graft function & poor renal allograft survival. This emphasizes the urgent need for plasma and urinary oxalate lowering therapies, and enhancing the bowel’s ability to secrete oxalate may effectively do so. We previously identified Oxalobacter formigenes (O. formigenes)-derived factors secreted in its culture conditioned medium (CM) which stimulated oxalate transport by human intestinal Caco2-BBE (C2) cells and reduced urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. Given their remarkable therapeutic potential, we now identified several proteins belonging to Sel1-like family as the major O. formigenes-derived secreted factors, and we determined the crystal structures for six proteins to better understand their function. Importantly, Sel1-14-derived small peptides P8 & P9 were identified as the major factors, with P8+9 closely recapitulate the CM’s effects, including acting through the oxalate transporters SLC26A2 & SLC26A6 and PKA activation. P8+9 also stimulate oxalate transport by human ileal and colonic organoids, confirming that these peptides work in human tissues. Collectively, the identification of these small peptides provide a great opportunity for developing a peptide-based novel therapeutic for hyperoxalemia, hyperoxaluria, and related disorders, impacting the outcomes of patients suffering from KS, primary hyperoxaluria, CKD, ADPKD, ESRD, and renal transplant recipients.

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Ramulus Mori (Sangzhi) Alkaloids (SZ-A) ameliorate non-diabetic chronic kidney disease by modulating fatty acid metabolism and restoring mitochondrial homeostasis in rats

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