Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease

Cansby, Emmelie; Caputo, Mara; Gao, Lei; Kulkarni, Nagaraj M.; Nerstedt, Annika; Ståhlman, Marcus; Borén, Jan; Porosk, Rando; Soomets, Ursel; Pedrelli, Matteo; Parini, Paolo; Marschall, Hanns‐Ulrich; Nyström, Jenny; Howell, Brian W.; Mahlapuu, Margit

doi:10.1172/jci.insight.140483

Cited by 16 publications

(8 citation statements)

References 68 publications

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“…71 Serine/threonine-protein kinase 25 promotes lipid deposition and renal injury by increasing the expression levels of fatty acid de novo synthesis genes, such as FASN and ACC1. 72 Enhanced uptake and disturbed export of lipid. CD36 is a major transporter for the uptake of FFAs and is widely expressed in the renal parenchymal cells, including TECs, macrophages, podocytes, mesangial cells, and endothelial cells.…”

Section: Signaling Pathways Related To Lipotoxicity In Chronic Kidney...mentioning

confidence: 99%

Signaling pathways of chronic kidney diseases, implications for therapeutics

Yuan

Tang

Zhang

2022

Sig Transduct Target Ther

115

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Chronic kidney disease (CKD) is a chronic renal dysfunction syndrome that is characterized by nephron loss, inflammation, myofibroblasts activation, and extracellular matrix (ECM) deposition. Lipotoxicity and oxidative stress are the driving force for the loss of nephron including tubules, glomerulus, and endothelium. NLRP3 inflammasome signaling, MAPK signaling, PI3K/Akt signaling, and RAAS signaling involves in lipotoxicity. The upregulated Nox expression and the decreased Nrf2 expression result in oxidative stress directly. The injured renal resident cells release proinflammatory cytokines and chemokines to recruit immune cells such as macrophages from bone marrow. NF-κB signaling, NLRP3 inflammasome signaling, JAK-STAT signaling, Toll-like receptor signaling, and cGAS-STING signaling are major signaling pathways that mediate inflammation in inflammatory cells including immune cells and injured renal resident cells. The inflammatory cells produce and secret a great number of profibrotic cytokines such as TGF-β1, Wnt ligands, and angiotensin II. TGF-β signaling, Wnt signaling, RAAS signaling, and Notch signaling evoke the activation of myofibroblasts and promote the generation of ECM. The potential therapies targeted to these signaling pathways are also introduced here. In this review, we update the key signaling pathways of lipotoxicity, oxidative stress, inflammation, and myofibroblasts activation in kidneys with chronic injury, and the targeted drugs based on the latest studies. Unifying these pathways and the targeted therapies will be instrumental to advance further basic and clinical investigation in CKD.

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Section: Signaling Pathways Related To Lipotoxicity In Chronic Kidney...mentioning

confidence: 99%

Signaling pathways of chronic kidney diseases, implications for therapeutics

Yuan

Tang

Zhang

2022

Sig Transduct Target Ther

115

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“…Diabetic kidney disease (DKD), or diabetic nephropathy, is one of the most fatal complications of diabetes mellitus, and it is the most prevailing element of end-stage renal disease ( Cansby et al, 2020 ). Metabolic changes caused by diabetes lead to proteinuria, progressive mesangial expansion, glomerular basement membrane thickening, tubulointerstitial fibrosis, and impaired renal function ( Alicic et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease

et al. 2021

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The gut microbiota plays a pivotal role in the onset and development of diabetes and its complications. Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite of certain nutrients, is associated with type 2 diabetes and its complications. Diabetic kidney disease (DKD) is one of the most serious microvascular complications. However, whether TMAO accelerates the development of DKD remains unclear. We tested the hypothesis that TMAO accelerates the development of DKD. A high-fat diet/low-dose streptozotocin-induced diabetes rat model was established, with or without TMAO in the rats’ drinking water. Compared to the normal rats, the DKD rats showed significantly higher plasma TMAO levels at the end of the study. TMAO treatment not only exacerbated the kidney dysfunction of the DKD rats, but also renal fibrosis. Furthermore, TMAO treatment activated the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome and resulted in the release of interleukin (IL)-1β and IL-18 to accelerate renal inflammation. These results suggested that TMAO aggravated renal inflammation and fibrosis in the DKD rats, which provides a new perspective to understand the pathogenesis of DKD and a potential novel target for preventing the progression of DKD.

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“…Paraffin-embedded kidney samples were cut into 4-μm-thick sections for hematoxylin and eosin (HE) staining and periodic acid-Schiff (PAS) staining to evaluate the incrassation of the glomerular mesangial matrix; the positive area was calculated as previously described [ 13 , 14 ]. Picrosirius red staining was used to detect renal fibrosis as previously reported [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

Combination of canagliflozin and puerarin alleviates the lipotoxicity to diabetic kidney in mice

Zhu

Zhou

Luo

et al. 2023

Korean J Physiol Pharmacol

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Diabetic kidney disease is one of the most serious complications of diabetes. Although diabetic kidney disease can be effectively controlled through strict blood glucose management and corresponding symptomatic treatment, these therapies cannot reduce its incidence in diabetic patients. The sodium-glucose cotransporter 2 (SGLT2) inhibitors and the traditional Chinese herb "Gegen" have been widely used in diabetes-related therapy. However, it remains unclear whether the combined use of these two kinds of medicines contributes to an increased curative effect on diabetic kidney disease. In this study, we examined this issue by evaluating the efficacy of the combination of puerarin, an active ingredient of Gegen, and canagliflozin, an SGLT2 inhibitor for a 12-week intervention using a mouse model of diabetes. The results indicated that the combination of puerarin and canagliflozin was superior to canagliflozin alone in improving the metabolic and renal function parameters of diabetic mice. Our findings suggested that the renoprotective effect of combined puerarin and canagliflozin in diabetic mice was achieved by reducing renal lipid accumulation. This study provides a new strategy for the clinical prevention and treatment of diabetic kidney disease. The puerarin and SGLT2 inhibitor combination therapy at the initial stage of diabetes may effectively delay the occurrence of diabetic kidney injury, and significantly alleviate the burden of renal lipotoxicity.

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Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease

Cited by 16 publications

References 68 publications

Signaling pathways of chronic kidney diseases, implications for therapeutics

Signaling pathways of chronic kidney diseases, implications for therapeutics

Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease

Combination of canagliflozin and puerarin alleviates the lipotoxicity to diabetic kidney in mice

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