• Animals
• Female
• Male
• Mice
• Antihypertensive Agents/therapeutic use
• Diabetes Mellitus, Type 2/drug therapy
• Fibrosis
• Glucose Transport Proteins, Facilitative/pharmacology
• Glucose Transport Proteins, Facilitative/therapeutic use
• Nephritis, Hereditary/drug therapy
• Nephritis, Hereditary/genetics
• Nephritis, Hereditary/pathology
• Ramipril/therapeutic use
• Receptors, Mineralocorticoid
• Renal Insufficiency, Chronic/drug therapy
• Renin-Angiotensin System
• Sodium
• Sodium-Glucose Transporter 2/pharmacology
• Sodium-Glucose Transporter 2/therapeutic use

Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes COL4A3, COL4A4 and COL4A5, that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis of population cohorts has revealed that it is the second most common inherited kidney disease after polycystic kidney disease. Renal involvement is the main manifestation, although it may have associated extrarenal manifestations such as hearing loss or ocular problems. The degree of expression of the disease changes according to the gene affected and other factors, known or yet to be known. The pathophysiology is not yet fully understood, although some receptors, pathways or molecules are known to be linked to the disease. There is also no specific treatment for Alport syndrome; the most commonly used are renin–angiotensin–aldosterone system inhibitors. In recent years, diagnosis has come a long way, thanks to advances in DNA sequencing technologies such as next-generation sequencing (NGS). Further research at the genetic and molecular levels in the future will complete the partial vision of the pathophysiological mechanism that we have, and will allow us to better understand what is happening and how to solve it.

• Alport syndrome
• COL4A
• chronic kidney disease
• collagen
• hereditary kidney disease

• Angiotensin-Converting Enzyme Inhibitors/therapeutic use
• Animals
• Collagen Type IV/genetics
• Ergocalciferols/therapeutic use
• High-Throughput Nucleotide Sequencing
• Humans
• Integrins/genetics
• Integrins/metabolism
• Laminin/genetics
• Laminin/metabolism
• Nephritis, Hereditary/diagnosis
• Nephritis, Hereditary/pathology
• Nephritis, Hereditary/therapy
• Polymorphism, Genetic

• disordered iron metabolism
• iron metabolism
• macrophage polarization

• Animals
• Homeostasis
• Humans
• Inflammation/immunology
• Inflammation/metabolism
• Iron/immunology
• Iron/metabolism
• Macrophage Activation
• Macrophages/immunology
• Macrophages/metabolism
• Phagocytosis

• CCL18
• CCL8
• cytokines
• inflammation
• kidney disease
• macrophages

• podocytes
• alport syndrome

• Animals
• Collagen Type IV/genetics
• Disease Models, Animal
• Disease Progression
• Genetic Background
• Genetic Predisposition to Disease
• Kidney/metabolism
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mutation
• Nephritis, Hereditary/genetics
• Nephritis, Hereditary/metabolism
• Podocytes/metabolism

• MC_UP_1502/1 Medical Research Council
• G0900747 Medical Research Council
• MC_U142684172 Medical Research Council
• G090074791070 Medical Research Council
• Wellcome Trust
• 090532/Z/09/Z Wellcome Trust
• RCUK | Medical Research Council (MRC)

• chronic kidney disease
• fibrosis
• inflammation
• macrophages
• tissue repair

• PDGF-C
• angiotensin
• angiotensinogen
• hypertension
• renal fibrosis

• Macrophage
• Macrophage polarization
• Macrophage-myofibroblast transition
• Renal fibrosis

• Animals
• Apoptosis
• Autoantigens/genetics
• Clodronic Acid/administration & dosage
• Clodronic Acid/pharmacology
• Clodronic Acid/therapeutic use
• Collagen Type IV/deficiency
• Collagen Type IV/genetics
• Disease Progression
• Drug Evaluation, Preclinical
• Female
• Kidney/pathology
• Kidney Failure, Chronic/etiology
• Liposomes
• Macrophages/drug effects
• Macrophages/pathology
• Male
• Mice
• Mice, 129 Strain
• Mice, Knockout
• Models, Animal
• Nephritis, Hereditary/drug therapy
• Nephritis, Hereditary/genetics
• Nephritis, Hereditary/immunology
• Nephritis, Hereditary/physiopathology
• Sex Characteristics

Alport syndrome (AS) is a hereditary nephritis caused by mutations in COL4A3, COL4A4 or COL4A5 encoding the type IV collagen α3, α4, and α5 chains, which are major components of the glomerular basement membrane. About 20 years have passed since COL4A3, COL4A4, and COL4A5 were identified and the first Alport mouse model was developed using a knockout approach. The phenotype of Alport mice is similar to that of Alport patients, including characteristic thickening and splitting of the glomerular basement membrane. Alport mice have been widely used to study the pathogenesis of AS and to develop effective therapies. In this review, the newer therapies for AS, such as pharmacological interventions, genetic approaches and stem cell therapies, are discussed. Although some stem cell therapies have been demonstrated to slow the renal disease progression in Alport mice, these therapies demand continual refinement as research advances. In terms of the pharmacological drugs, angiotensin-converting enzyme inhibitors have been shown to be effective in Alport mice. Novel therapies that can provide a better outcome or lead to a cure are still awaited.

• Alport syndrome
• Angiotensin-converting enzyme
• Genetic
• Hereditary nephritis
• Pharmacological
• Renal injury
• Stem cell therapy

Are there common pathways underlying the broad spectrum of tissue pathologies that develop upon injuries and from subsequent tissue remodeling? Here, we explain the pathophysiological impact of a set of evolutionary conserved danger control programs for tissue pathology. These programs date back to the survival benefits of the first multicellular organisms upon traumatic injuries by launching a series of danger control responses, i.e., 1. Haemostasis, or clotting to control bleeding; 2. Host defense, to control pathogen entry and spreading; 3. Re-epithelialisation, to recover barrier functions; and 4. Mesenchymal, to repair to regain tissue stability. Taking kidney pathology as an example, we discuss how clotting, inflammation, epithelial healing, and fibrosis/sclerosis determine the spectrum of kidney pathology, especially when they are insufficiently activated or present in an overshooting and deregulated manner. Understanding the evolutionary benefits of these response programs may refine the search for novel therapeutic targets to limit organ dysfunction in acute injuries and in progressive chronic tissue remodeling.

• cell therapy
• kidney disease
• macrophages

Alport syndrome is a hereditary glomerulopathy with proteinuria and nephritis caused by defects in genes encoding type IV collagen in the glomerular basement membrane. All male and most female patients develop end-stage renal disease. Effective treatment to stop or decelerate the progression of proteinuria and nephritis is still under investigation. Here we showed that combination treatment of mild electrical stress (MES) and heat stress (HS) ameliorated progressive proteinuria and renal injury in mouse model of Alport syndrome. The expressions of kidney injury marker neutrophil gelatinase-associated lipocalin and pro-inflammatory cytokines interleukin-6, tumor necrosis factor-α and interleukin-1β were suppressed by MES+HS treatment. The anti-proteinuric effect of MES+HS treatment is mediated by podocytic activation of phosphatidylinositol 3-OH kinase (PI3K)-Akt and heat shock protein 72 (Hsp72)-dependent pathways in vitro and in vivo. The anti-inflammatory effect of MES+HS was mediated by glomerular activation of c-jun NH₂-terminal kinase 1/2 (JNK1/2) and p38-dependent pathways ex vivo. Collectively, our studies show that combination treatment of MES and HS confers anti-proteinuric and anti-inflammatory effects on Alport mice likely through the activation of multiple signaling pathways including PI3K-Akt, Hsp72, JNK1/2, and p38 pathways, providing a novel candidate therapeutic strategy to decelerate the progression of patho-phenotypes in Alport syndrome.

• Alport
• chronic kidney disease
• collagen
• crescent
• glomerulosclerosis
• parietal epithelial cells

We review the current literature on the molecular mechanisms involved in the pathogenesis of acute kidney injury induced by plasma mediators released by mechanical ventilation. A comprehensive literature search in the PubMed database was performed and articles were identified that showed increased plasma levels of mediators where the increase was solely attributable to mechanical ventilation. A subsequent search revealed articles delineating the potential effects of each mediator on the kidney or kidney cells. Limited research has focused specifically on the relationship between mechanical ventilation and acute kidney injury. Only a limited number of plasma mediators has been implicated in mechanical ventilation-associated acute kidney injury. The number of mediators released during mechanical ventilation is far greater and includes pro- and anti-inflammatory mediators, but also mediators involved in coagulation, fibrinolysis, cell adhesion, apoptosis and cell growth. The potential effects of these mediators is pleiotropic and include effects on inflammation, cell recruitment, adhesion and infiltration, apoptosis and necrosis, vasoactivity, cell proliferation, coagulation and fibrinolysis, transporter regulation, lipid metabolism and cell signaling. Most research has focused on inflammatory and chemotactic mediators. There is a great disparity of knowledge of potential effects on the kidney between different mediators. From a theoretical point of view, the systemic release of several mediators induced by mechanical ventilation may play an important role in the pathophysiology of acute kidney injury. However, evidence supporting a causal relationship is lacking for the studied mediators.