Background: Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health burdens closely related to metabolic syndrome. A link between CKD and NASH has been assumed; however, the underlying mechanism is still unknown. Ectopic lipid deposition (ELD) in the hepatocyte results in endoplasmic reticulum (ER) stress, which plays an important role in the development of steatohepatitis. ELD is also assumed to play a role in the development of kidney injury. We aimed to investigate the role of ELD and ER stress in the development of CKD, and evaluate the efficacy of a sodium glucose cotransporter-2 inhibitor, ipragliflozin. Methods: Male FLS-ob/ob mice that closely imitate the pathophysiology of NASH were treated with vehicle or ipragliflozin. Metabolic characteristics, histology of the kidney, ER stress, and apoptotic signals were evaluated. Results: The serum triglyceride was significantly lower in mice treated with ipragliflozin. Ipragliflozin reduced ELD in renal tubules. Ipragliflozin also reduced the expression levels of GRP78 and CHOP, apoptotic cells, and interstitial fibrosis. Conclusions: ELD induced kidney injury through ER stress. Ipragliflozin improved the pathogenesis of CKD by reducing ELD and ER stress in NASH-model mice. Our results suggest ipragliflozin has therapeutic effect on CKD in NASH.

Background: Rapidly progressive glomerulonephritis (RPGN) is a syndrome characterized by a rapid decline in renal function that often causes end-stage renal disease. Although it is important to predict renal outcome in RPGN before initiating immunosuppressive therapies, no simple prognostic indicator has been reported. The aim of this study was to investigate the associations of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to renal outcomes in patients with RPGN. Methods: Forty-four patients with a clinical diagnosis of RPGN who underwent renal biopsy were enrolled. The relationships between NLR and PLR and renal outcome after 1 year were investigated. Results: NLR and PLR were significantly higher in patients with preserved renal function in comparison to patients who required maintenance hemodialysis (p < 0.05 and p < 0.01, respectively). An NLR of 4.0 and a PLR of 137.7 were the cutoff values for renal outcome (area under the curve, 0.782 and 0.819; sensitivity, 78.4% and 89.2%; specificity, 71.4% and 71.4%, respectively). Furthermore, an NLR of 5.0 could predict recovery from renal injury in patients requiring hemodialysis (area under the curve, 0.929; sensitivity, 83.3%; specificity, 85.7%). Conclusion: NLR and PLR could be candidates for predicting renal outcomes in patients with RPGN.

Steatosis, or ectopic lipid deposition, is the fundamental pathophysiology of non-alcoholic steatohepatitis and chronic kidney disease. Steatosis in the renal tubule causes endoplasmic reticulum (ER) stress, leading to kidney injury. Thus, ER stress could be a therapeutic target in steatonephropathy. Five-aminolevulinic acid (5-ALA) is a natural product that induces heme oxygenase (HO)-1, which acts as an antioxidant. This study aimed to investigate the therapeutic potential of 5-ALA in lipotoxicity-induced ER stress in human primary renal proximal tubule epithelial cells. Cells were stimulated with palmitic acid (PA) to induce ER stress. Cellular apoptotic signals and expression of genes involved in the ER stress cascade and heme biosynthesis pathway were analyzed. The expression of glucose-regulated protein 78 (GRP78), a master regulator of ER stress, increased significantly, followed by increased cellular apoptosis. Administration of 5-ALA induced a remarkable increase in HO-1 expression, thus ameliorating PA-induced GRP78 expression and apoptotic signals. BTB and CNC homology 1 (BACH1), a transcriptional repressor of HO-1, was significantly downregulated by 5-ALA treatment. HO-1 induction attenuates PA-induced renal tubular injury by suppressing ER stress. This study demonstrates the therapeutic potential of 5-ALA against lipotoxicity through redox pathway.