Kidney disease: new technologies translate mechanisms to cure

O’Toole, John F.; Sedor, John R.

doi:10.1172/jci76825

Cited by 17 publications

(11 citation statements)

References 88 publications

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“…Obesity, well known as a major public health issue worldwide, has been reported to be associated with many diseases, such as hypertension and type 2 diabetes mellitus [ 1 – 3 ]. Accumulating evidence suggests that obesity is also a major risk factor for the development and progression of chronic kidney disease (CKD) [ 3 – 5 ]. Along with the development of obesity, fast body weight gain increases tubular sodium reabsorption in the kidney, which in turn leads to renal vasodilation and glomerular hyperfiltration and eventually results in an increased glomerular filtration rate.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen Sulfide Mitigates Kidney Injury in High Fat Diet‐Induced Obese Mice

Gao

et al. 2016

Oxidative Medicine and Cellular Longevity

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Obesity is prevalent worldwide and is a major risk factor for the development and progression of kidney disease. Hydrogen sulfide (H2S) plays an important role in renal physiological and pathophysiological processes. However, whether H2S is able to mitigate kidney injury induced by obesity in mice remains unclear. In this study, we demonstrated that H2S significantly reduced the accumulation of lipids in the kidneys of high fat diet- (HFD-) induced obese mice. The results of hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining showed that H2S ameliorated the kidney structure, decreased the extent of interstitial injury, and reduced the degree of kidney fibrosis in HFD-induced obese mice. We found that H2S decreased the expression levels of tumor necrosis factor-α, interleukin- (IL-) 6, and monocyte chemoattractant protein-1 but increased the expression level of IL-10. Furthermore, H2S treatment decreased the protein expression of p50, p65, and p-p65 in the kidney of HFD-induced obese mice. In conclusion, H2S is able to mitigate renal injury in HFD-induced obese mice through the reduction of kidney inflammation by downregulating the expression of nuclear factor-kappa B. H2S or its releasing compounds may serve as a potential therapeutic molecule for obesity-induced kidney injury.

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Section: Introductionmentioning

confidence: 99%

Hydrogen Sulfide Mitigates Kidney Injury in High Fat Diet‐Induced Obese Mice

Gao

et al. 2016

Oxidative Medicine and Cellular Longevity

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“…During the past decades, the mechanisms for kidney fibrosis have been deeply investigated, but few therapeutic strategies are available to efficiently halt the progression of interstitial fibrosis and chronic kidney diseases 5 6 . Recently, Qin et al .…”

mentioning

confidence: 99%

Quercetin Inhibits Fibroblast Activation and Kidney Fibrosis Involving the Suppression of Mammalian Target of Rapamycin and β-catenin Signaling

Ren

Liu

et al. 2016

Sci Rep

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Quercetin, a flavonoid found in a wide variety of plants and presented in human diet, displays promising potential in preventing kidney fibroblast activation. However, whether quercetin can ameliorate kidney fibrosis in mice with obstructive nephropathy and the underlying mechanisms remain to be further elucidated. In this study, we found that administration of quercetin could largely ameliorate kidney interstitial fibrosis and macrophage accumulation in the kidneys with obstructive nephropathy. MTORC1, mTORC2, β-catenin as well as Smad signaling were activated in the obstructive kidneys, whereas quercetin could markedly reduce their abundance except Smad3 phosphorylation. In cultured NRK-49F cells, quercetin could inhibit α-SMA and fibronectin (FN) expression induced by TGFβ1 treatment. MTORC1, mTORC2, β-catenin and Smad signaling pathways were stimulated by TGFβ1 at a time dependent manner. Similar to those findings in the obstructive kidneys, mTORC1, mTORC2 and β-catenin, but not Smad signaling pathways were remarkably blocked by quercetin treatment. Together, these results suggest that quercetin inhibits fibroblast activation and kidney fibrosis involving a combined inhibition of mTOR and β-catenin signaling transduction, which may act as a therapeutic candidate for patients with chronic kidney diseases.

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“…Therefore, the protection and restoration of podocytes have been deemed as important for DN treatment. Owing to the limitation of conventional treatments in affecting podocyte injury, novel therapies and targeted treatments are urgently needed 30 . Many studies have demonstrated the ameliorative effects of pancreatic islet transplantation on renal injury and podocyte damage in DN animal models 31 .…”

Section: Discussionmentioning

confidence: 99%

Aberrant activation of Notch-1 signaling inhibits podocyte restoration after islet transplantation in a rat model of diabetic nephropathy

Zhang

et al. 2018

Cell Death Dis

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Signaling abnormalities play important roles during podocyte injury and have been indicated as crucial events for triggering many glomerular diseases. There is emerging evidence demonstrating significant improvements in preventing renal injury and restoring podocytes after islet transplantation. However, whether signaling abnormalities affect the therapeutic efficacy of islet transplantation remain unclear. This study was established to investigate the impact of Notch-1 signaling activation on renal injury and podocyte restoration after islet transplantation. Experiments were performed in vivo and in vitro under conditions of diabetic nephropathy and high-glucose medium, respectively. Podocyte injury in vitro was induced by high-glucose concentration, and expression levels of genes associated with the Notch-1 pathway were also regulated by Jagged-1/FC and N-[N-(3,5-Difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester (DAPT). Podocytes were co-cultured with islets to investigate the protective effect of islets in high-glucose conditions. Histopathological staining and transmission electron microscopy were performed to assess pathological changes in podocytes in glomeruli. The results from this study showed that Notch-1 signaling in podocytes was significantly decreased by functional islet cells in vivo and in vitro. Compared with the co-cultured group and transplanted group, highly activated Notch-1 signaling significantly moderated the effect of islets in affecting podocyte restoration and renal injury. Renal damage and podocyte injury were alleviated after DAPT treatment. Furthermore, the balance between apoptosis and autophagy was diverse under different treatments. All the data in this study showed that highly activated Notch-1 signaling could affect the therapeutic efficacy of islet transplantation on renal injury and podocyte restoration in high-glucose conditions. The balance between apoptosis and autophagy was also closely associated with the degree of podocyte restoration. This finding may suggest that the in vivo microenvironment plays a critical role in podocyte restoration after islet transplantation, which provides a promising and individual assessment and targeting treatment for different diabetic nephropathy patients after islet transplantation into the future.

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Kidney disease: new technologies translate mechanisms to cure

Cited by 17 publications

References 88 publications

Hydrogen Sulfide Mitigates Kidney Injury in High Fat Diet‐Induced Obese Mice

Hydrogen Sulfide Mitigates Kidney Injury in High Fat Diet‐Induced Obese Mice

Quercetin Inhibits Fibroblast Activation and Kidney Fibrosis Involving the Suppression of Mammalian Target of Rapamycin and β-catenin Signaling

Aberrant activation of Notch-1 signaling inhibits podocyte restoration after islet transplantation in a rat model of diabetic nephropathy

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