Mechanisms of podocyte injury and implications for diabetic nephropathy

Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine. The kidneys filter approximately 180 l of fluids everyday; however, there is no loss of proteins into urine as the glomerular filtration barrier (GFB) retains 99.99% of plasma proteins. Alterations in the GFB result in the development of proteinuria, ranging from albuminuria to massive nephrotic syndrome. Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN), obesity-related nephropathy, and an important feature of chronic kidney diseases (CKDs). In addition, in patients with CKD, albuminuria is a predictor of progression towards end-stage renal disease (ESRD) and is associated with an increased risk of cardiovascular diseases. Glomerular podocytes are a component of the GFB and podocyte injury is the main cause of albuminuria development. Herein, we will describe patterns of podocyte damage and review underlying mechanisms, focussing particularly on DN.