Mechanisms of tubulointerstitial injury in the kidney: final common pathways to end-stage renal failure

There are many different glomerular disorders, including glomerulonephritis, diabetic nephropathy, and hypertensive nephrosclerosis. However, once glomerular damage reaches a certain threshold, the progression of renal disease is consistent and irreversible. Recent studies emphasized the crucial role of tubulointerstitial injury as a mediator of progression of kidney disease. One common mechanism that leads to renal failure via tubulointerstitial injury is massive proteinuria. Accumulating evidence suggests critical effects of filtered macromolecules on tubular cells, including lysosomal rupture, energy depletion, and tubular injury directly induced by specific components such as complement components. Another common mechanism is chronic hypoxia in the tubulointerstitium. Tubulointerstitial damage results in the loss of peritubular capillaries, impairing blood flow delivery. Interstitial fibrosis also impairs oxygen diffusion and supply to tubular cells. This induces chronic hypoxia in this compartment, rendering a vicious cycle. Development of novel therapeutic approaches against these final common pathways will enable us to target any types of renal disease.     

Ultrastructural changes in the glomerular filtration barrier and occurrence of proteinuria in Chinese patients with type 2 diabetic nephropathy

AimDiabetic nephropathy (DN) is one of the most important causes of end stage renal disease in the world. Its hallmark is proteinuria. Therefore, we set out to clarify the structural changes that occur in the glomerular filtration barrier in Chinese patients with true type 2 diabetic nephropathy, and to examine the relationship between these structural changes and proteinuria.Methods42 Chinese patients with true T2DN were divided into three groups according to urinary protein excretion. Glomerular volume, endothelial cell density, endothelial cell number, glomerular basement membrane (GBM) width, podocyte density, podocyte number and foot process width were evaluated using light and electron microscopic morphometry.ResultGlomerular volume and endothelial cell number were increased in diabetic patients, but there was no difference between patients with respect to the degree of proteinuria. As proteinuria progressed, endothelial cell density remained unchanged, while the glomerular basement membrane (GBM) and podocyte foot process width increased, podocyte density and number decreased.ConclusionsPodocyte and GBM change more obviously during the development of proteinuria. Besides, proteinuria was inversely related to podocyte density, and directly related to GBM and glomerular volume.     

Endothelial cell-specific overexpression of endothelial nitric oxide synthase in Ins2Akita mice exacerbates diabetic nephropathy

Previous studies demonstrated that global deficiency of eNOS in diabetic mice exacerbated renal lesions and that overexpression of eNOS may protect against tissue injury. Our study revealed for the first time overexpression of eNOS leads to disease progression rather than protection. Transgenic mice selectively expressing eNOS in endothelial cells (eNOSTg) were cross bred with Ins2Akita type-1 (AK) diabetic mice to generate eNOS overexpressing eNOSTg/AK mice. Wild type, eNOSTg, AK and eNOSTg/AK mice were assessed for kidney function and blood glucose levels. Remarkably, overexpressing eNOSTg mice showed evidence of unpredicted glomerular injury with segmental mesangiolysis and occasional microaneurysms. Notably, in eNOSTg/AK mice overexpression of eNOS led to increased glomerular/endothelial injury that was associated with increased superoxide levels and renal dysfunction. Results indicate for the first time that overexpressing eNOS in endothelial cells cannot ameliorate diabetic lesions, but paradoxically leads to progression of nephropathy likely due to eNOS uncoupling and superoxide upsurge. This novel finding has a significant impact on current therapeutic strategies to improve endothelial function and prevent progression of diabetic renal disease. Further, the eNOSTg/AK model developed in this study has significant translational potentials for elucidating the underlying mechanism implicated in the deflected function of eNOS in diabetic nephropathy.     

Temporal Profile of Diabetic Nephropathy Pathologic Changes

Diabetic nephropathy, by far, is the most common cause of end stage renal disease in the US and many other countries. In type 1 diabetes, the natural history of diabetic nephropathy is tightly linked to evolution of classic lesions of the disease, namely glomerular basement membrane thickening, increased mesangial matrix, and reduced glomerular filtration surface density. These lesions progress in parallel and correlate with increased albumin excretion rate and reduced glomerular filtration rate across a wide range of renal function. In fact, the vast majority of the variances of albumin excretion and glomerular filtration rates can be explained by these glomerular lesions alone in type 1 diabetic patients. Although, classic lesions of diabetic nephropathy, indistinguishable from those of type 1 diabetes, also occur in type 2 diabetes, renal lesions are more heterogeneous in type 2 diabetic patients with some patients developing more advanced vascular or chronic tubulointerstitial lesions than diabetic glomerulopathy. More research biopsy longitudinal studies, especially in type 2 diabetic patients, are needed to better understand various pathways of renal injury in diabetic nephropathy.     

足细胞与糖尿病肾病关系的若干研究进展

足细胞在维持肾小球滤过屏障完整性及限制血浆蛋白的滤出方面发挥重要作用,足细胞的损伤可部分解释肾小球滤过屏障结构及功能的改变的原因。在糖尿病肾病早期,足细胞损伤已出现,并可进一步导致。肾脏损伤。本文就足细胞与糖尿病肾病中若干研究进展作简要综述。     

Trophic factors and cytokines in early diabetic glomerulopathy

The intent of this review is to focus on recent advances in the understanding of the factors responsible for the progressive pathologic features of diabetic kidney disease, with special attention to various growth factors and cytokines that appear to be important in this process. In addition, emphasis is centered on relatively early stages of the disease, because animal models have been most helpful to date in understanding this stage of the disease process. Although tubulointerstitial changes are of critical importance in the progression of diabetic nephropathy, especially in the evolution to end-stage renal disease, there is a general consensus that glomerular pathology occurs first. Therefore, attention is limited to factors that may be important in the development of early diabetic glomerulopathy, including transforming growth factor-beta (TGF-beta), insulin-like growth factor (IGF)-I, vascular endothelial growth factor (VEGF)-A, and connective tissue growth factor (CTGF).     

Interaction of haemodynamic and metabolic pathways in the genesis of diabetic nephropathy

Clinical diabetic nephropathy is characterized by an earlier functional phase in which hyperglycaemia is accompanied by an increased glomerular filtration rate and microalbuminuria; the persistence of this high-flow and high-pressure state, added to a poor control of hyperglycaemia, fosters renal damage and proteinuria, accompanied by a decline in glomerular filtration rate and progression to end-stage renal disease. In this review, we present glucose transporter 1 (GLUT-1) as a novel link that connects the glomerular hyperfiltration (hypertension) state and the complex cascade of events that leads to nephropathy. The interplay between angiotensin II and nitric oxide, and its interactions with reactive oxygen species, are also discussed, in an attempt to provide an integrated view of the pathophysiology of diabetic nephropathy.     

Podocytes as a target of insulin

Diabetic nephropathy (DN) presents with a gradual breakdown of the glomerular filtration barrier to protein, culminating in widespread glomerular damage and renal failure. The podocyte is the central cell of the glomerular filtration barrier, and possesses unique architectural and signaling properties guided by the expression of key podocyte specific proteins. How these cellular features are damaged by the diabetic milieu is unclear, but what is becoming increasingly clear is that damage to the podocyte is a central event in DN. Here we present accumulating evidence that insulin action itself is important in podocyte biology, and may be deranged in the pathomechanism of early DN. This introduces a rationale for therapeutic intervention to improve podocyte insulin sensitivity early in the presentation of DN.     

The pathogenesis and diagnosis of acute kidney injury in multiple myeloma

Renal failure remains a principal cause of morbidity for patients with multiple myeloma. Once reversible factors such as hypercalcemia have been corrected, the most common cause of severe renal failure in these patients is a tubulointerstitial pathology that results from the very high circulating concentrations of monoclonal immunoglobulin free light chains. These endogenous proteins can result in isolated proximal tubule cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy (myeloma kidney). Less frequently, high levels of free light chains can lead to immunoglobulin light chain amyloidosis and light chain deposition disease, although these conditions are usually associated with insidious progression of renal failure rather than acute kidney injury. Unless there is rapid intervention, progressive and irreversible damage occurs, particularly interstitial fibrosis and tubular atrophy. Despite advances in our understanding of the pathogenesis of these processes there has been a gap in translating these achievements into improved patient outcomes. The International Kidney and Monoclonal Gammopathy Research Group was formed to address this need. In this Review, we discuss the mechanisms of disease and diagnostic approaches to patients with acute kidney injury complicating multiple myeloma.     

艾塞那肽对糖尿病肾病小鼠足细胞的保护作用

目的:探讨艾塞那肽对糖尿病肾病小鼠足细胞的作用。方法:通过给予C57BL/6J小鼠高脂饮食并注射链脲佐菌素建立糖尿病肾病模型,按随机数字表法将其分为糖尿病肾病对照组(DN组, n＝8)、艾塞那肽干预组(DN＋Ex组, n＝8)。同时将普通饲料喂养的C57BL/6J小鼠作为正常对照组(NC组, ...     

糖尿病糖脂代谢紊乱与足细胞损害的实验研究

目的　观察糖脂代谢紊乱对糖尿病大鼠肾小球滤过屏障外层足细胞的影响 ,以探讨糖尿病肾病的发病机制。方法　采用链脲佐菌素诱导糖尿病大鼠模型 ,喂养 5周后 ,测定血糖、糖化血红蛋白、甘油三酯、总胆固醇、血肌酐、尿素氮和尿白蛋白排泄率 ,应用免疫组化检测肾小球足细胞损伤标志蛋白 -desmin的表达 ,同时利用透射电子显微镜观察肾小球足细胞超微结构。结果　糖尿病大鼠血糖、糖化血红蛋白、总胆固醇、血肌酐、尿素氮、尿白蛋白排泄率水平明显升高 (P <0 .0 5 ) ,肾小球内desmin蛋白表达上调 ,足细胞部分足突融合 ;同时 ,两组间血甘油三酯水平无显著性差异 (P >0 .0 5 )。结论　糖脂代谢紊乱可导致糖尿病大鼠肾小球滤过屏障外层足细胞明显损害 ,尿白蛋白排泄率增加 ,这可能是糖尿病肾脏损害、蛋白尿出现的机制之一     

Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade

Aims/hypothesis. Changes in podocyte number and morphology have been implicated in the pathogenesis of proteinuria and the progression of human and experimental kidney disease. This study sought to examine podocyte foot process and slit pore architecture in experimental diabetic nephropathy and to determine whether such changes were modified with renoprotective intervention by blockade of the renin-angiotensin system. Methods. The number of filtration slits per 100 μm of glomerular basement membrane was assessed by transmission electron microscopy and quantitated histomorphometrically in control animals and in rats with 24 weeks of streptozotocin-induced diabetes. Diabetic rats were either untreated or received the angiotensin converting enzyme inhibitor ramipril, or the angiotensin II type 1 receptor antagonist, valsartan. Results. When compared with control animals, diabetes was associated with a decrease in the number of slit pores per unit length of glomerular basement membrane, indicative of podocyte foot process broadening. Both ramipril and valsartan attenuated these ultrastructural changes to a similar degree. These differences remained after correcting for glomerular volume as a possible confounding variable. Conclusion/interpretation. Preservation of podocyte architecture could contribute to the renoprotective effects of renin-angiotensin system blockade in diabetic nephropathy. [Diabetologia (2001) 44: 878–882] Received: 19 January 2001 and in revised form: 28 March 2001     

Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy

Microalbuminuria is the earliest detectable clinical abnormality in diabetic glomerulopathy. On a molecular level, metabolic pathways activated by hyperglycemia, glycated proteins, hemodynamic factors, and oxidative stress are key players in the genesis of diabetic kidney disease. A variety of growth factors and cytokines are then induced through complex signal transduction pathways. Transforming growth factor-beta 1 (TGF-beta1) has emerged as an important downstream mediator for the development of renal hypertrophy and the accumulation of mesangial extracellular matrix components, but there is limited evidence to support its role in the development of albuminuria. The loss of proteoglycans in the glomerular basement membrane (GBM) has been recently questioned as causative of the albuminuria, and current research has focused on the podocyte as a central target for the effects of the metabolic milieu in the development and progression of diabetic albuminuria. Podocyte-derived vascular endothelial growth factor (VEGF), a permeability and angiogenic factor whose expression is increased in diabetic kidney disease, is perhaps a major mediator of the increased protein filtration. Decreased podocyte number and/or density as a result of apoptosis or detachment, GBM thickening with altered matrix composition, and a reduction in nephrin protein in the slit diaphragm with podocyte foot process effacement, all comprise the principal features of diabetic podocytopathy that clinically manifests as albuminuria and proteinuria. Many of these events are mediated by angiotensin II whose local concentration is stimulated by high glucose, mechanical stretch, and proteinuria itself. Angiotensin II in turn stimulates podocyte-derived VEGF, suppresses nephrin expression, and induces TGF-beta1 leading to podocyte apoptosis and fostering the development of glomerulosclerosis. Proteinuria can then induce in tubular cells a genetic program leading to tubulointerstitial inflammation, fibrosis and tubular atrophy. Besides direct effects of albuminuria on tubular cells, pathophysiological changes in the ultrafiltration barrier lead to an increased tubular filtration of various growth factors (TGF-beta1, insulin-like growth factor I) that may further alter the function of tubular cells. Moreover, angiotensin II also stimulates uptake of ultrafiltered proteins into tubular cells and enhances the production of proinflammatory and profibrotic cytokines within the cells. Migration of macrophages and other inflammatory cells into the tubulointerstitium occurs. Increased synthesis and decreased turnover of extracellular matrix proteins in tubular cells and interstitial fibroblasts contribute to interstitial fibrosis. In addition, under locally high concentrations of angiotensin II and TGF-beta1, tubular cells may change their phenotype and become fibroblasts by a process called epithelial to mesenchymal transition (EMT) which contributes to interstitial fibrosis and tubular atrophy because of vanishing epithelia cells. An alternative explanation for the development of albuminuria in diabetic nephropathy that involves primarily an abnormality in tubular handling of ultrafiltered proteins has also been suggested, but these changes are not necessarily exclusive of the altered properties of glomerular ultrafiltration barrier.     

Role of angiotensin II in the development of nephropathy and podocytopathy of diabetes

Diabetic kidney disease is the leading cause of end-stage renal disease worldwide. Podocytes are highly differentiated, pericyte-like cells that are essential for normal function of the kidney filter. Loss of podocytes is a hallmark of progressive kidney diseases including diabetic nephropathy. Podocytes are a direct target for angiotensin II - mediated injury by altered expression and distribution of podocyte proteins. Additionally, angiotensin II promotes podocyte injury indirectly by increasing calcium influx and production of reactive oxygen species. Notwithstanding the convincing rationale for angiotensin II blockade as a treatment modality, the incidence of diabetes-related end stage renal disease has increased steadily despite widespread use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Recently published clinical trials have rekindled a debate on the safety and efficacy of dual blockade of the renin-angiotensin system (RAS). This review summarizes the rationale for blockade of angiotensin II as a therapeutic target in treating diabetic kidney disease, including the critical role played by podocytes. Recent relevant clinical trials on the role of RAS blockade in the treatment of diabetic kidney disease are discussed.     

Drug-Induced Glomerular Disease: Attention Required!

Drugs and toxins frequently are associated with the development of various types of acute kidney disease and CKD. Although medications are a widely known cause of tubulointerstitial damage, drug-related glomerular injury is not well appreciated but nonetheless, important. Glomerular damage that occurs after exposure to medications can be caused by direct cellular injury involving the mesangial, endothelial, or visceral epithelial cells (podocytes). Examples include nodular glomerulosclerosis associated with smoking and endothelial injury with thrombotic microangiopathy from a number of medications. Podocyte injury with the development of a minimal change or FSGS lesion has also been described with various medications. Glomerulopathies may also be associated with drug-induced immune-mediated processes. Through various pathways, drugs may promote the formation of a number of antibodies, which may, ultimately, affect the glomerulus. Examples include lupus-like renal lesions and ANCA-related pauci-immune vasculitis. It is critical to recognize these conditions early, because in many patients, there is improvement in renal parameters on stopping the offending medication.     

Increased glomerular cell (podocyte) apoptosis in rats with streptozotocin-induced diabetes mellitus: role in the development of diabetic glomerular disease

Aims/hypothesis Podocyte loss by apoptosis, in addition to favouring progression of established diabetic nephropathy, has been recently indicated as an early phenomenon triggering the initiation of glomerular lesions. This study aimed to assess the rate of glomerular cell death and its relationship with renal functional, structural and molecular changes in rats with experimental diabetes. Methods Male Sprague–Dawley rats with streptozotocin-induced diabetes and coeval non-diabetic control animals were killed at 7 days and at 2, 4 and 6 months for the assessment of apoptosis, renal function, renal structure and the expression of podocyte markers and apoptosis- and cell cycle-related proteins. Results Glomerular cell apoptosis was significantly increased in diabetic vs non-diabetic rats at 4 months and to an even greater extent at 6 months, with podocytes accounting for 70% of apoptosing cells. The increase in apoptosis was preceded by increases in proteinuria, albuminuria and mean glomerular and mesangial areas, and by reductions in glomerular cell density and content of synaptopodin and Wilms’ tumour protein-1. It coincided with the development of mesangial expansion and glomerular sclerosis, and with the upregulation/activation both of tumour protein p53, which increased progressively throughout the study, and of p21 (also known as cyclin-dependent kinase inhibitor 1A, CIP1 and WAF1), which peaked at 4 months and decreased thereafter. Conclusions/interpretation Glomerular cell (podocyte) apoptosis is not an early feature in the course of experimental diabetic glomerulopathy, since it is preceded by glomerular hypertrophy, which may decrease glomerular cell density to the point of inducing compensatory podocyte hypertrophy. This is associated with reduced podocyte protein expression (podocytopathy) and proteinuria, and ultimately results in apoptotic cell loss (podocytopenia), driving progression to mesangial expansion and glomerular sclerosis. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Oxidative stress in early diabetic nephropathy: fueling the fire

Diabetic nephropathy is a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease worldwide. The treatment costs of diabetes mellitus and its complications represent a huge burden on health-care expenditures, creating a major need to identify modifiable factors concerned in the pathogenesis and progression of diabetic nephropathy. Chronic hyperglycemia remains the primary cause of the metabolic, biochemical and vascular abnormalities in diabetic nephropathy. Promotion of excessive oxidative stress in the vascular and cellular milieu results in endothelial cell dysfunction, which is one of the earliest and most pivotal metabolic consequences of chronic hyperglycemia. These derangements are caused by excessive production of advanced glycation end products and free radicals and by the subjugation of antioxidants and antioxidant mechanisms. An increased understanding of the role of oxidative stress in diabetic nephropathy has lead to the exploration of a number of therapeutic strategies, the success of which has so far been limited. However, judicious and timely use of current therapies to maintain good glycemic control, adequate blood pressure and lipid levels, along with lifestyle measures such as regular exercise, optimization of diet and smoking cessation, may help to reduce oxidative stress and endothelial cell dysfunction and retard the progression of diabetic nephropathy until more definitive therapies become available.