We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, the leading cause of end-stage kidney disease. mRNA expression profiling from proteinuric mouse glomeruli was linked to Connectivity Map databases, identifying HDAC1 and HDAC2 with the differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment with valproic acid (a class I HDAC inhibitor) or SAHA (a pan-HDAC inhibitor) mitigated the degree of proteinuria and glomerulosclerosis, leading to a striking increase in survival. Podocyte HDAC1 and HDAC2 activities were increased in mice podocytopathy models, and podocyte-associated Hdac1 and Hdac2 genetic ablation improved proteinuria and glomerulosclerosis. Podocyte early growth response 1 (EGR1) was increased in proteinuric patients and mice in an HDAC1- and HDAC2-dependent manner. Loss of EGR1 in mice reduced proteinuria and glomerulosclerosis. Longitudinal analysis of the multicenter Veterans Aging Cohort Study demonstrated a 30% reduction in mean annual loss of estimated glomerular filtration rate, and this effect was more pronounced in proteinuric patients receiving valproic acid. These results strongly suggest that inhibition of HDAC1 and HDAC2 activities may suppress the progression of human proteinuric kidney diseases through the regulation of EGR1.

Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid to the tubulointerstitial region, which accounts for the majority of the kidney volume. DKD’s tubulointerstitial lesions are characterized by inflammation, fibrosis, and loss of kidney function, and recent studies indicate that these lesions may occur earlier than glomerular lesions. Evidence has shown that inflammatory mechanisms in the tubulointerstitium play a critical role in the development and progression of these lesions. Apart from the renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors and new types of mineralocorticoid receptor antagonists have emerged as effective ways to treat DKD. Moreover, researchers have proposed potential targeted therapies, such as inhibiting pro-inflammatory cytokines and modulating T cells and macrophages, among others. These therapies have demonstrated promising results in preclinical studies and clinical trials, suggesting their potential to treat DKD-induced tubulointerstitial lesions effectively. Understanding the immune-inflammatory mechanisms underlying DKD-induced tubulointerstitial lesions and developing targeted therapies could significantly improve the treatment and management of DKD. This review summarizes the latest advances in this field, highlighting the importance of focusing on tubulointerstitial inflammation mechanisms to improve DKD outcomes.

The glomerular filtration barrier, comprising the inner layer of capillary fenestrated endothelial cells, outermost podocytes, and the glomerular basement membrane between them, plays a pivotal role in kidney function. Podocytes, terminally differentiated epithelial cells, are challenging to regenerate once injured. They are essential for maintaining the integrity of the glomerular filtration barrier. Damage to podocytes, resulting from intrinsic or extrinsic factors, leads to proteinuria in the early stages and eventually progresses to chronic kidney disease (CKD). Immune-mediated podocyte injury is a primary pathogenic mechanism in proteinuric glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and lupus nephritis with podocyte involvement. An extensive body of evidence indicates that podocytes not only contribute significantly to the maintenance of the glomerular filtration barrier and serve as targets of immune responses but also exhibit immune cell-like characteristics, participating in both innate and adaptive immunity. They play a pivotal role in mediating glomerular injury and represent potential therapeutic targets for CKD. This review aims to systematically elucidate the mechanisms of podocyte immune injury in various podocyte lesions and provide an overview of recent advances in podocyte immunotherapy. It offers valuable insights for a deeper understanding of the role of podocytes in proteinuric glomerular diseases, and the identification of new therapeutic targets, and has significant implications for the future clinical diagnosis and treatment of podocyte-related disorders.

Idiopathic membranous nephropathy (IMN) is a pathological pattern of glomerular damage caused by an autoimmune response. Immune complex deposition, thickness of glomerular basement membrane, and changes in the podocyte morphology are responsible for the development of proteinuria, which is caused by the targeted binding of auto-antibodies to podocytes. Several auto-antigens have recently been identified in IMN, including M-type receptor for secretory phospholipase A2 (PLA2R1), thrombospondin type-1 domain-containing 7A (THSD7A), and neural epidermal growth factor-like 1 protein (NELL-1). The measurement of peripheral circulating antibodies has become an important clinical reference index. However, some clinical features of IMN remain elusive and need to be further investigated, such as the autoimmunity initiation, IgG4 predominance, spontaneous remission, and the unique glomerular lesion. As these unresolved issues are closely related to clinical practice, we have proposed a hypothetical pathogenesis model of IMN. Induced by environmental stimuli or other causes, the PLA2R1 antigen and/or THSD7A antigen exposed to extrarenal tissues, such as lungs, then produce the auto-antibodies that target and cause damage to the podocytes in circulation. In this review, we highlighted the potential association between environmental stimuli, immune activity, and glomerular lesions, the underlying basis for spontaneous immune and proteinuria remission.

The progression of proteinuric kidney diseases is associated with podocyte loss, but the mechanisms underlying this process remain unclear. Podocytes reenter the cell cycle to repair double-stranded DNA breaks. However, unsuccessful repair can result in podocytes crossing the G₁/S checkpoint and undergoing abortive cytokinesis. In this study, we identified Pfn1 as indispensable in maintaining glomerular integrity — its tissue-specific loss in mouse podocytes resulted in severe proteinuria and kidney failure. Our results suggest that this phenotype is due to podocyte mitotic catastrophe (MC), characterized histologically and ultrastructurally by abundant multinucleated cells, irregular nuclei, and mitotic spindles. Podocyte cell cycle reentry was identified using FUCCI2aR mice, and we observed altered expression of cell-cycle associated proteins, such as p21, p53, cyclin B1, and cyclin D1. Podocyte-specific translating ribosome affinity purification and RNA-Seq revealed the downregulation of ribosomal RNA-processing 8 (Rrp8). Overexpression of Rrp8 in Pfn1-KO podocytes partially rescued the phenotype in vitro. Clinical and ultrastructural tomographic analysis of patients with diverse proteinuric kidney diseases further validated the presence of MC podocytes and reduction in podocyte PFN1 expression within kidney tissues. These results suggest that profilin1 is essential in regulating the podocyte cell cycle and its disruption leads to MC and subsequent podocyte loss.

Evidence for reduced expression of cyclin G associated kinase (GAK) in glomeruli of patients with chronic kidney disease was observed in the Nephroseq human database, and GAK was found to be associated with the decline in kidney function. To examine the role of GAK, a protein that functions to uncoat clathrin during endocytosis, we generated podocyte-specific Gak -knockout mice ( Gak -KO), which developed progressive proteinuria and kidney failure with global glomerulosclerosis. We isolated glomeruli from the mice carrying the mutation to perform messenger RNA profiling and unearthed evidence for dysregulated podocyte calpain protease activity as an important contributor to progressive podocyte damage. Treatment with calpain inhibitor III specifically inhibited calpain-1/-2 activities, mitigated the degree of proteinuria and glomerulosclerosis, and led to a striking increase in survival in the Gak -KO mice. Podocyte-specific deletion of Capns1 , essential for calpain-1 and calpain-2 activities, also improved proteinuria and glomerulosclerosis in Gak -KO mice. Increased podocyte calpain activity–mediated proteolysis of IκBα resulted in increased NF-κB p65–induced expression of growth arrest and DNA-damage-inducible 45 beta in the Gak -KO mice. Our results suggest that loss of podocyte-associated Gak induces glomerular injury secondary to calcium dysregulation and aberrant calpain activation, which when inhibited, can provide a protective role.