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Introduction
Diabetic nephropathy (DN) is an important endocrine metabolic dysfunctional disease and the leading cause of end-stage renal disease worldwide (1). Increasing evidence indicates that injury, detachment, apoptosis and loss of podocytes are observed in humans with DN and in DN animal models (2–4). Podocytes are key in maintaining the integrity of the glomerular filtration barrier, together with mesangial cells, and have been reported to be important for the progression of diabetic kidney disease (5). In patients with type I and II diabetes mellitus, the density of podocytes is significantly reduced in those who have had the diabetes for a short duration prior to the onset of microalbuminuria (6). A correlation between the rate of albumin excretion and the reduction in podocyte number has been demonstrated in rats with streptozotocin-induced diabetes mellitus (7). In addition, high glucose (HG) provokes adhesion capacity and phenotypic alterations in cultured podocytes (8). Taken together, these data indicate that podocyte injury is closely associated with hyperglycemia. Although there is considerable evidence suggesting that chronic hyperglycemia is the primary cause of podocyte injury, the underlying molecular mechanisms of hyperglycemia-induced podocyte injury remain to be elucidated.
Endoplasmic reticulum (ER) is a central organelle engaged in lipid synthesis, protein folding and maturation (9). A variety of toxic insults, including hypoxia (10), glucocorticoids (11) and HG (12), can disturb ER function, and result in ER stress. There is increasing evidence that ER stress is crucial in the regulation of apoptosis (13), with a previous study reporting that ER stress is triggered in angiotensin II-treated podocytes (14). In addition, palmitate induces ER calcium depletion and apoptosis in mouse podocytes following mitochondrial oxidative stress (9), and HG induces the apoptosis of podocytes through ER stress in vivo and in vitro (15,16). These results suggest that ER stress is involved in the pathogenesis of podocyte dysfunction and is being recognized as an emerging target for DN therapy.
Huaiqihuang (HQH) is predominantly composed of Trametes robiniophila Murr, Fructus Lycii and Polygonatum sibiricum, and has been widely used for the treatment of primary nephrotic syndrome (17). In renal tissues of rats with adriamycin-induced nephrosis, HQH can maintain the integrity of the slit diaphragm in podocytes, alleviate lesions of the glomerular filtration membrane, and decrease proteinuria by upregulating...