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Cisplatin nephrotoxicity is a critical limitation of solid cancer treatment. Until now, the complex interplay of various pathophysiological mechanisms leading to proximal tubular cell apoptosis after cisplatin exposure has not been fully understood. In our study, we assessed the role of the autophagy-related protein BECLIN1 (ATG6) in cisplatin-induced acute renal injury (AKI)—a candidate protein involved in autophagy and with putative impact on apoptosis by harboring a B-cell lymphoma 2 (BCL2) interaction site of unknown significance. By using mice with heterozygous deletion of Becn1, we demonstrate that reduced intracellular content of BECLIN1 does not impact renal function or autophagy within 12 months. However, these mice were significantly sensitized towards cisplatin-induced AKI, and by using Becn1+/−;Sglt2-Cre;Tomato/EGFP mice with subsequent primary cell analysis, we confirmed that nephrotoxicity depends on proximal tubular BECLIN1 content. Mechanistically, BECLIN1 did not impact autophagy or primarily the apoptotic pathway. In fact, a lack of BECLIN1 sensitized mice towards cisplatin-induced ER stress. Accordingly, the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blunted cisplatin-induced cell death in Becn1 heterozygosity. In conclusion, our data first highlight a novel role of BECLIN1 in protecting against cellular ER stress independent from autophagy. These novel findings open new therapeutic avenues to intervene in this important intracellular stress response pathway with a promising impact on future AKI management.

Podocytes are highly-specialized epithelial cells essentially required for the generation and the maintenance of the kidney filtration barrier. This elementary function is directly based on an elaborated cytoskeletal apparatus establishing a complex network of primary and secondary processes. Here, we identify the actin-bundling protein allograft-inflammatory-inhibitor 1 like (AIF1L) as a selectively expressed podocyte protein in vivo. We describe the distinct subcellular localization of AIF1L to actin stress fibers, focal adhesion complexes and the nuclear compartment of podocytes in vitro. Genetic deletion of AIF1L in immortalized human podocytes resulted in an increased formation of filopodial extensions and decreased actomyosin contractility. By the use of SILAC based quantitative proteomics analysis we describe the podocyte specific AIF1L interactome and identify several components of the actomyosin machinery such as MYL9 and UNC45A as potential AIF1L interaction partners. Together, these findings indicate an involvement of AIF1L in the stabilization of podocyte morphology by titrating actomyosin contractility and membrane dynamics.

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.

Vascular endothelial growth factor A (VEGFA) secretion from podocytes is crucial for maintaining endothelial integrity within the glomerular filtration barrier. However, until now, the molecular mechanisms underlying podocyte secretory function remained unclear. Through podocyte-specific deletion of BECLIN1 (ATG6 or Becn1), a key protein in autophagy initiation, we identified a major role for this molecule in anterograde Golgi trafficking. The Becn1-deficient podocytes displayed aberrant vesicle formation in the trans-Golgi network (TGN), leading to dramatic vesicle accumulation and complex disrupted patterns of intracellular vesicle trafficking and membrane dynamics. Phenotypically, podocyte-specific deletion of Becn1 resulted in early-onset glomerulosclerosis, which rapidly progressed and dramatically reduced mouse life span. Further, in vivo and in vitro studies clearly showed that VEGFA secretion, and thereby endothelial integrity, greatly depended on BECLIN1 availability and function. Being the first to demonstrate the importance of a secretory pathway for podocyte integrity and function, we identified BECLIN1 as a key component in this complex cellular process. Functionally, by promoting VEGFA secretion, a specific secretory pathway emerged as an essential component for the podocyte-endothelial crosstalk that maintains the glomerular filtration barrier.

Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The multipronged drug approach targeting blood pressure and serum levels of glucose, insulin, and lipids fails to fully prevent the onset and progression of diabetic nephropathy. Therefore, a new therapeutic target to combat diabetic nephropathy is required. Autophagy is a catabolic process that degrades damaged proteins and organelles in mammalian cells and plays a critical role in maintaining cellular homeostasis. The accumulation of proteins and organelles damaged by hyperglycemia and other diabetes-related metabolic changes is highly associated with the development of diabetic nephropathy. Recent studies have suggested that autophagy activity is altered in both podocytes and proximal tubular cells under diabetic conditions. Autophagy activity is regulated by both nutrient state and intracellular stresses. Under diabetic conditions, an altered nutritional state due to nutrient excess may interfere with the autophagic response stimulated by intracellular stresses, leading to exacerbation of organelle dysfunction and diabetic nephropathy. In this review, we discuss new findings showing the relationships between autophagy and diabetic nephropathy and suggest the therapeutic potential of autophagy in diabetic nephropathy.

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.

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.

Summary Extending healthy lifespan is an emerging issue in an aging society. This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)‐induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. Simple DR significantly extended lifespan and ameliorated age‐related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA. Simple DR prevented the age‐dependent decrease in slow‐twitch muscle fiber function but reduced absolute fast‐twitch muscle fiber function. DR‐induced fast‐twitch muscle fiber dysfunction was improved by recovering either dietary NEAAs or EAAs. In the ad libitum‐fed and the DR plus EAA groups, the renal content of methionine, an EAA, was significantly higher, accompanied by lower renal production of hydrogen sulfide (H2S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet‐restricted aged mice, which were accompanied by a recovery in H2S production capacity and lower oxidative stress. These data imply that a dietary approach could combat kidney aging and prolong lifespan, while preventing muscle weakness, and suggest that renal methionine metabolism and the trans‐sulfuration pathway could be therapeutic targets for preventing kidney aging and subsequently promoting healthy aging.