Journal Article

Brown adipose tissue alleviates podocyte apoptosis through NRG4 in a male mouse model of diabetic kidney disease

Li, Shu-guang, Shi, Ling-feng, Wei, Wei, Peng, Xiang-yan, Xu, Jin-ling, Tong, Jia-yue, Cheng, Yang-yang, Zhang, Jia-jia, Wang, Zhong-jing, Zhang, Li-ming, Yue, Ling, Ding, Sheng, Xiang, Lin, Xiang, Guang-da, Meng, Bi-ying

2025

Overview

Aims/hypothesis Brown adipose tissue (BAT) consumes excess energy through heat production by uncoupling protein 1 (UCP1) to regulate the metabolic profile, but the UCP1-independent mechanisms of BAT, such as in endocrine function, are largely unknown. Our previous study showed that BAT-derived neuregulin 4 (NRG4) displays anti-atherosclerotic properties. Thus, we hypothesised that BAT could regulate diabetic nephropathy, a diabetic microvascular complication, via NRG4. Methods To investigate the influence of NRG4 from BAT on podocyte apoptosis, both loss- and gain-of-function approaches were used in in vivo experiments. Diabetic nephropathy models were created using BAT-specific Nrg4 -knockout (BKO) mice, global Nrg4 -knockout (KO) mice and wild-type (WT) mice. In in vitro studies, podocytes (MPC5) were exposed to glucose and recombinant NRG4 (rNrg4). Additionally, brown adipocytes were co-cultured with MPC5 podocytes using a transwell system. The expression levels of proteins associated with podocyte apoptosis and signalling pathways were measured. Results BAT-specific NRG4 deficiency aggravated podocyte apoptosis (increased by 47.46%) and increased the urinary albumin/creatinine ratio (increased by 41.71%), decreased nephrin expression and increased desmin expression. As expected, these changes were reversed by NRG4 replenishment using adeno-associated virus–NRG4 interscapular BAT injection and BAT transplantation assays in KO mice. Additionally, co-culture experiments demonstrated that brown adipocytes from WT mice could alleviate high-glucose-induced podocyte apoptosis. In in vitro experiments, recombinant NRG4 inhibited high-glucose-induced podocyte apoptosis. Mechanistically, the Akt–glycogen synthase kinase 3 β (GSK-3β) pathway is crucial for the protection that BAT-derived NRG4 provides to podocytes in diabetic nephropathy. Conclusions/interpretation Our data show that BAT had a protective effect on podocyte apoptosis in diabetic nephropathy through BAT-derived NRG4, and the Akt–GSK‑3β signalling pathway may mediate the inhibition of BAT-derived NRG4 on podocyte apoptosis in diabetic nephropathy. Graphical Abstract

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V
• Subject: Adipocytes / Adipose tissue (brown) / Adipose Tissue, Brown - metabolism / AKT protein / Animal models / Animals / Apoptosis / Apoptosis - genetics / Apoptosis - physiology / Arteriosclerosis / Body fat / Creatinine / Desmin / Diabetes / Diabetes mellitus / Diabetic Nephropathies - metabolism / Diabetic Nephropathies - pathology / Diabetic nephropathy / Disease Models, Animal / Glucose / Glycogen / Glycogen synthase kinase 3 / Human Physiology / Internal Medicine / Kidney diseases / Kinases / Male / Medicine / Medicine & Public Health / Metabolic Diseases / Mice / Mice, Inbred C57BL / Mice, Knockout / Microvasculature / Nephropathy / Neuregulin / Neuregulins - genetics / Neuregulins - metabolism / Podocytes - metabolism / Signal Transduction / Uncoupling protein 1