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Saturated fatty acid (SFA)-related lipotoxicity is a pathogenesis of diabetes-related renal proximal tubular epithelial cell (PTEC) damage, closely associated with a progressive decline in renal function. This study was designed to identify a free fatty acid (FFA) metabolism-related enzyme that can protect PTECs from SFA-related lipotoxicity. Among several enzymes involved in FFA metabolism, we identified stearoyl-CoA desaturase-1 (SCD1), whose expression level significantly decreased in the kidneys of high-fat diet (HFD)-induced diabetic mice, compared with non-diabetic mice. SCD1 is an enzyme that desaturates SFAs, converting them to monounsaturated fatty acids (MUFAs), leading to the formation of neutral lipid droplets. In culture, retrovirus-mediated overexpression of SCD1 or MUFA treatment significantly ameliorated SFA-induced apoptosis in PTECs by enhancing intracellular lipid droplet formation. In contrast, siRNA against SCD1 exacerbated the apoptosis. Both overexpression of SCD1 and MUFA treatment reduced SFA-induced apoptosis via reducing endoplasmic reticulum stress in cultured PTECs. Thus, HFD-induced decrease in renal SCD1 expression may play a pathogenic role in lipotoxicity-induced renal injury, and enhancing SCD1-mediated desaturation of SFA and subsequent formation of neutral lipid droplets may become a promising therapeutic target to reduce SFA-induced lipotoxicity. The present study provides a novel insight into lipotoxicity in the pathogenesis of diabetic nephropathy.

Background/Aim Most patients with proteinuria are considered to have typical diabetic nephropathy (DN). However, when proteinuria occurs without diabetic retinopathy, with hematuria, or persists despite strict glycemic and blood pressure control, it is considered atypical for DN and warrants further evaluation for non‐DN via kidney biopsy. Nevertheless, comprehensive information on renal histopathology and prognosis following kidney biopsy remains limited. This study aimed to clarify these issues through a retrospective analysis. Methods Among 490 patients who underwent kidney biopsy at Shiga University of Medical Science Hospital between 2013 and 2024, 51 Japanese patients with type 2 diabetes who met at least one criterion for proteinuria atypical for DN were included. Pre‐ and post‐biopsy changes in proteinuria levels and eGFR decline rate, as well as renal histology, were analyzed. Results Among the 51 patients, 17 (33.3%) were histologically diagnosed with typical DN, whereas 34 (66.7%) were diagnosed with non‐DN, including membranous nephropathy, immunoglobulin A (IgA) nephropathy, renal sclerosis, interstitial nephritis, vasculitis, and others. Compared with the DN group, patients with non‐DN were significantly older and had a lower prevalence of diabetic retinopathy. Additionally, the non‐DN group showed significant improvements in both proteinuria levels and in the eGFR decline following biopsy and appropriate disease‐specific therapy. Conclusion A kidney biopsy identified a wide range of kidney diseases as the underlying causes of atypical proteinuria in DN, particularly in elderly patients, thereby improving renal outcomes. These findings underscore the clinical importance of heightened awareness of atypical proteinuria in diabetes management, particularly in aging populations.

Background Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy. Methods Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations. Results The 20 patients consisted of 11 males and 9 females, of mean age 61.6 ± 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin E 2 concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR. Conclusions Loxoprofen-containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases.

Accumulating evidence suggests health benefits of ketone bodies, and especially for longevity. However, the precise role of endogenous ketogenesis in mammalian life span, and the safety and efficacy of the long‐term exogenous supplementation of ketone bodies remain unclear. In the present study, we show that a deficiency in endogenous ketogenesis, induced by whole‐body Hmgcs2 deletion, shortens life span in mice, and that this is prevented by daily ketone body supplementation using a diet containing 1,3‐butanediol, a precursor of β‐hydroxybutyrate. Furthermore, feeding the 1,3‐butanediol‐containing diet from early in life increases midlife mortality in normal mice, but in aged mice it extends life span and prevents the high mortality associated with atherosclerosis in ApoE‐deficient mice. By contrast, an ad libitum low‐carbohydrate ketogenic diet markedly increases mortality. In conclusion, endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double‐edged sword with respect to survival, depending on the method of administration and health status. The present study demonstrates that endogenous ketogenesis is essential for long‐term mammalian survival, which was revealed by a study using Hmgcs2−/− mice, and that dietary administration of 1,3‐butanediol (1,3‐BD), a precursor of β‐OHB, increases midlife mortality in normal mice, but extends life span in aged mice or atherosclerotic mice. By contrast, ad libitum low‐carbohydrate ketogenic diet increases mortality in any mouse models. Thus, ketone bodies represent a double‐edged sword for mammalian survival.