Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy

Disruption of lysosomal homeostasis contributes to the tubulopathy of diabetic nephropathy; however, its underlying mechanisms remain unclear. Herein, we report that decreased activity of transcription factor EB (TFEB) is responsible for the disturbed lysosome biogenesis and clearance in this pathological process. This was confirmed by the findings that insufficient lysosomal replenishment and damaged lysosomal clearance coincided with TFEB inactivation, which was mediated by mTOR hyperactivation in the renal tubular epithelial cells (TECs) of diabetic nephropathy. Furthermore, either TFEB overexpression or pharmacological activation of TFEB enhanced lysosomal clearance via promoting lysosomal biogenesis and protected TECs by reducing apoptosis in vitro. In addition, pharmacological activation of TFEB attenuated renal tubule injury, apoptosis, and inflammation in db/db mice. In conclusion, diabetes-induced mTOR activation represses TFEB function, thereby perturbing lysosomal homeostasis through impairing lysosomal biogenesis and clearance in TECs. Moreover, TFEB activation protects TECs from diabetic injuries via restoring lysosomal homeostasis.

Kidney-Targeted Redox Scavenger Therapy Prevents Cisplatin-Induced Acute Kidney Injury

Cisplatin-induced acute kidney injury (CI-AKI) is a significant co-morbidity of chemotherapeutic regimens. While this condition is associated with substantially lower survival and increased economic burden, there is no pharmacological agent to effectively treat CI-AKI. The disease is hallmarked by acute tubular necrosis of the proximal tubular epithelial cells primarily due to increased oxidative stress. We investigated a drug delivery strategy to improve the pharmacokinetics of an approved therapy that does not normally demonstrate appreciable efficacy in CI-AKI, as a preventive intervention. In prior work, we developed a kidney-selective mesoscale nanoparticle (MNP) that targets the renal proximal tubular epithelium. Here, we found that the nanoparticles target the kidneys in a mouse model of CI-AKI with significant damage. We evaluated MNPs loaded with the reactive oxygen species scavenger edaravone, currently used to treat stroke and ALS. We found a marked and significant therapeutic benefit with edaravone-loaded MNPs, including improved renal function, which we demonstrated was likely due to a decrease in tubular epithelial cell damage and death imparted by the specific delivery of edaravone. The results suggest that renal-selective edaravone delivery holds potential for the prevention of acute kidney injury among patients undergoing cisplatin-based chemotherapy.

Oxalate Activates Autophagy to Induce Ferroptosis of Renal Tubular Epithelial Cells and Participates in the Formation of Kidney Stones

Renal tubular epithelial cell damage is the basis for the formation of kidney stones. Oxalate can induce human proximal tubular (HK-2) cells to undergo autophagy and ferroptosis. The present study was aimed at investigating whether the ferroptosis of HK-2 cells induced by oxalate is caused by the excessive activation of autophagy. We treated HK-2 cells with 2 mmol/L of oxalate to establish a kidney stone model. First, we tested the degree of oxidative damage and the level of autophagy and ferroptosis in the control group and the oxalate intervention group. We then knocked down and overexpressed the BECN1 gene and knocked down the NCOA4 gene in HK-2 cells, followed by redetection of the above indicators. We confirmed that oxalate could induce autophagy and ferroptosis in HK-2 cells. Moreover, after oxalate treatment, overexpression of the BENC1 gene increased cell oxidative damage and ferroptosis. In addition, knockdown of NCOA4 reversed the effect of oxalate-induced ferroptosis in HK-2 cells. Our results show that the effects of oxalate on the ferroptosis of HK-2 cells are caused by the activation of autophagy, and knockdown of the NCOA4 could ameliorate this effect.

Gambaran Histologi Ren Tikus Putih (Rattus norvegicus L.) Hiperglikemia Setelah Pemberian Ekstrak Etanol Daun Mimba (Azadirachta Indica A. Juss)

Diabetes melitus merupakan penyakit kelainan metabolic yang ditandai dengan hiperglikemia kronis yang disebabkan tidak cukupnya produksi insulin dan resistensi insulin. Diabetes telah diketahui dapat menyebabkan komplikasi berupa kerusakan pada jaringan ginjal. Mimba (Azadirachta indica A.Juss) memiliki kandungan antioksidan flavonoid yang mampu menangkal radikal bebas dan memperbaiki jaringan ginjal yang rusak akibat diabetes. Penelitian ini menggunakan 18 tikus putih yang menjadi 6 kelompok perlakuan. P0 (kontrol normal) merupakan tukus normal diberi aquades. P1(Kontrol negatif) merupakan tikus hiperglikemia diberi aquades. P2 (kontrol positif) merupakan tikus hiperglikemia diberi glibenklamid dosis 2,25 mg/ kg BB. P3, P4, dan P5 merupakan tikus hiperglikemia yang diberi ekstrak etanol daun mimba dosis 100, 200, dan 400 mg/kg BB. Data penelitian kemudian dianalisis dengan uji Anova. Untuk data yang tidak terdistribusi normal diuji dengan uji Kruskal-Wallis. Hasil menunjukkan bahwa pemberian ekstrak etanol daun mimba tidak memberikan pengaruh nyata terhadap bobot ginjal, konsumsi air minum, diameter glomerulus, ruang kapsula bowman, tebal sel epitel tubulus proksimal, dan tebal sel epitel tubulus distal. Kesimpulan dari penelitian ini adalah ekstrak etanol daun mimba mampu melindungi jaringan ginjal tikus putih dari paparan hiperglikemia Diabetes is a metabolic disorder that treats chronic hyperglycemia caused by insufficient insulin production and insulin resistance. Diabetes has been known to cause complications in the form of damage to kidney tissue. Neem (Azadirachta indica A.Juss) has flavonoid antioxidants that can ward off free radicals and repair kidney tissue damaged by diabetes. The purpose of the study was to examine the ethanol extract of neem leaves repairing kidney tissue. The study used 18 albino rats were divided into 6 treatment groups. P1 (negative control) was a hyperglycemic rats group were given distilled water. P2 (positive control) was a hyperglycemic rats were given 2.25 mg/kg BW of glibenclamide. P3, P4, and P5 were rats were given 100, 200, and 400 mg/kg BW of ethanolic neem leaf extract The research data were analyzed by ANOVA. The non-normally distributed data were analyzed by Kruskal-Wallis. The results showed that the ethanol extract of neem leaves had no significant effect on kidney weight, water consumption, glomerular diameter, bowman's capsule space, proximal tubular epithelial cell thickness, and distal tubular epithelial cell thickness. The conclusion of this study was the ethanol extract of neem leaves was able to protect the kidney tissue of white rats from hyperglycemia.