Current Diabetes Reviews - Volume 7, Issue 1, 2011

Diabetic nephropathy (DN) affects both patient with type 1 and type 2 diabetes and represents a major burden to public health cost [1]. Tight glycemic and blood pressure control can dramatically slow the progression of the disease, particularly when diagnosed and intervened upon in the early stages [2]. However, a definitive cure remains to be found, and a large number of patients progress towards end-stage renal disease despite the currently employed measures. Finding a cure is hindered by the multiplicity of pathogenetic pathways, some already identified and others waiting to be discovered. An early and key event in the development of DN is the loss of podocytes from the kidney glomerulus. Podocytes are highly specialized cells that form foot processes and the glomerular slit diaphragm (SD) [3], a complex cellular organization that prevents the development of proteinuria [4]. The podocyte SD is composed of an ever increasing number of molecules that are finely interconnected and functionally dependent on the integrity of the actin cytoskeleton [5]. Most of the molecules that compose the SD have initially been thought to be primarily structural molecules, but it has become clear that each of these can initiate a cascade of signaling events that affect podocyte function [6]. A major research focus has been placed on how locally initiated events lead to podocyte damage in diabetes. In addition, the evidence that podocytes express receptors for many circulating hormones has suggested that a more complex cross talk between the kidney filtration barrier and other organs may occur in health and disease. This hot topic issue of CDR reviews the clinical and experimental evidence that hormonal derangements that characterize diabetes may be associated with the severity of proteinuria, which may be caused by a change in the ability of podocytes to respond to hormones such as insulin, sex hormones, growth hormone, adipokines, aldosterone, prorenin, angiotensin II, and Vitamin D. We selected hormones for which both podocyte receptor expression and clinical relevance have been suggested by prior studies. We excluded other hormones/parahormones that are most likely additional important modulator of podocytes function, such as free fatty acids (FFA), lipoproteins, adrenocorticotropic hormone (ACTH), growth hormone releasing hormone (GHRH), and thyroid hormones as we believe more studies are needed to support their specific function in DN. Campbell et al. review the role of angiotensin II as a modulator of proteinuria and podocyte malfunction in diabetes. In particular, the mechanisms by which local activation of the renin angiotensin system (RAS) in podocytes may lead to altered expression and distribution of slit diaphragm components are discussed. Nagase highlights the intriguing possibility that the anti-proteinuric effect of mineralocorticoid receptor (MR) antagonists may be linked to modulation of MR signaling in podocytes, which could be mediated by aldosterone binding to the MR receptor or through ligand-independent activation of MR by Rac 1, a small GTPase implicated in podocyte function. Ichihara et al. appraise the role of prorenin in the pathogenesis of DN and podocyte malfunction in diabetes and examine the experimental evidence that a decoy peptide that competitively inhibits the binding of prorenin to the (pro)renin receptor protects from the development of albuminuria in DN. This finding is highly relevant clinically, particularly in light of the recent evidence that podocytes express prorenin receptor and that prorenin receptor expression is modulated in the hyperfiltering kidney. Both local angiotensin II dependent and independent mechanisms of action are discussed. Given that insulin resistance correlates with the development of albuminuria in both diabetic and non diabetic patients [7], Coward et al. assess the clinical and experimental evidence that insulin resistance and hyperinsulinemia may play a pathogenetic role in the development of podocytopathy and proteinuria in DN. Insights gained may lead to the preferential utilization of selective hypoglycemic agents when trying to achieve superior renoprotection for an equal hemoglobin A1C target. The subsequent articles focus on hormones targeting nuclear receptors, namely estrogens and Vitamin D. Doublier et al. discuss the role of estrogens in the progression of diabetes-induced kidney injury and the effects of estrogens in podocyte signaling and survival. It is interesting to note that an intracrine mechanism of estrogen action in the diabetic kidney may occur: this recent finding adds complexity to how sex hormones and aromatase activity influence the development of DN [8]. Dr. Li discusses the intriguing possibility that the antiproteinuric effect observed in vitamin D treated patients and experimental animals might be related to a direct effect of Vitamin D on important signaling cascades in podocytes, such as the RAS and Wnt/b-catenin pathways. This review sheds light on novel functions of vitamin D that are beyond the traditional regulation of calcium and phosphorus metabolism. In order to underline the importance of a cross talk between different organs affected by diabetes, Mathew et al. review the role of adipokines in the development of the kidney disease observed in diabetes and obesity, with a focus on podocyte biology. The clinical evidence correlating serum levels of adipokines and macrovascular and microvascular complications is also addressed....

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.

Aldosterone has emerged as a deleterious hormone in the kidney, for example as a potent inducer of proteinuria. We identified the podocyte, the final filtration barrier in the glomerulus, as a novel target of aldosterone. Activation of the mineralocorticoid receptor (MR) in the podocyte disrupts the filtration barrier and induces proteinuria. Recent clinical and experimental studies have shown the efficacy of MR antagonism in reducing albuminuria in patients or rodent models of type 1 and type 2 diabetes. We assessed the pathogenic role of aldosterone in SHR/NDmcr-cp, a rat model of type 2 diabetes/metabolic syndrome. Podocyte injury and proteinuria were early manifestations of nephropathy in this model, and were exacerbated by high-salt feeding. Inappropriate activation of the aldosterone/MR system, possibly via adipocytederived aldosterone releasing factors, underlay the renal damage. Furthermore, we identified Rac1, a Rho family small GTPase, as a novel ligand-independent activator of MR. This alternative pathway of MR activation, indeed, contributed to podocyte injury in proteinuric kidney disease. In conclusion, MR can be activated by several different pathways, both aldosterone- dependently and -independently, leading to podocyte impairment and progression of proteinuric kidney disease. MR antagonists are promising anti-proteinuric drugs in diabetes, although hyperkalemia is a concern.

High plasma prorenin levels predict the onset of microvascular complications, such as albuminuria/proteinuria, in diabetic patients. In diabetic rats with elevated plasma prorenin levels, treatment with HRP, which competitively inhibits the binding of prorenin to the (pro)renin receptor [(P)RR] as a decoy peptide, significantly prevented the development of albuminuria/proteinuria and glomerulosclerosis, suggesting that (P)RR-bound prorenin plays a significant role in the pathogenesis of diabetic nephropathy. Recently, the presence of (P)RR in podocytes, which represent one of the glomerular filtration barriers, has been reported. Although podocytes are subjected to both high glucose levels and mechanical stretching caused by glomerular hyperfiltration under diabetic conditions, the expression of (P)RR is reportedly regulated by high glucose levels in in vitro mesangial cells and the in vivo kidneys of diabetic rats, whereas mechanical stretching is up-regulated by (P)RR expression in human podocytes. In addition, prorenin treatment not only leads to the generation of intracellular angiotensin (Ang)II, but also activates the phosphorylation of ERK via (P)RR in a manner that acts independently of AngII in human podocytes. Thus, the upregulation of prorenin and (P)RR in podocytes as a result of glomerular hyperfiltration might play an important role in the development of albuminuria/proteinuria via the generation of intracellular AngII and the stimulation of (P)RR-dependent intracellular signals. Further inquiry regarding podocyte (P)RR intracellular signal transduction will be needed to develop a new therapeutic approach targeting podocyte (P)RR in patients with diabetic nephropathy.

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.

It is generally accepted that estrogens affect and modulate the development and progression of chronic kidney diseases (CKD) not related to diabetes. Clinical studies have indeed demonstrated that the severity and rate of progression of renal damage tends to be greater among men, compared with women. Experimental studies also support the notion that female sex is protective and male sex permissive, for the development of CKD in non-diabetics, through the opposing actions of estrogens and testosterone. However, when we consider diabetes-induced kidney damage, in the setting of either type 1 or type 2 diabetes, the contribution of gender to the progression of renal disease is somewhat uncertain. Previous studies on the effects of estrogens in the pathogenesis of progressive kidney damage have primarily focused on mesangial cells. More recently, data on the effects of estrogens on podocytes, the cell type whose role may include initiation of progressive diabetic renal disease, became available. The aim of this review will be to summarize the main clinical and experimental data on the effects of estrogens on the progression of diabetes-induced kidney injury. In particular, we will highlight the possible biological effects of estrogens on podocytes, especially considering those critical for the pathogenesis of diabetic kidney damage.

Vitamin D deficiency is a prominent feature of chronic kidney disease (CKD) even in its early stages. While vitamin D deficiency leads to mineral imbalance and bone problems in CDK patients, it also accelerates the progression of kidney disease. Ever since the observation that vitamin D analogs reduce proteinuria in CKD patients, it has been postulated that podocytes are major target of the reno-protective action of vitamin D. Recent large randomized clinical trials have confirmed the potent anti-proteinuric activity of vitamin D therapy. Studies from various animal models of kidney disease have demonstrated that vitamin D prevents podocyte injury and cell loss, promotes the expression of slit diaphragm proteins and maintains the integrity of the glomerular filtration barrier. Emerging experimental data suggest that vitamin D may protect podocytes by targeting multiple pathways, including the renin-angiotensin system, Wnt/β-catenin pathway and pro-apoptotic pathway.

Obesity is a risk factor for both de novo disease and as a complication of existing chronic kidney disease. Obesity related disease is characterized by albuminuria, glomerulomegaly and secondary focal glomerulosclerosis. Traditionally altered renal hemodynamics causing hyperfiltration and upregulated renin angiotensin system have been associated with these changes. Recently identified circulating factors produced by fat stores such as adiponectin, leptin and inflammatory markers have shown to directly affect the cells in the renal glomeruli and cause pathological changes. Weight loss, blockade of the renin angiotensin system and restoration of adipokine levels may be beneficial to ameliorate the progression of obesity related disease.

Involvement of the growth hormone (GH) / insulin-like growth factor 1 (IGF-1) axis in the pathogenesis of diabetic nephropathy (DN) is strongly suggested by studies investigating the impact of GH excess and deficiency on renal structure and function. GH excess in both the human (acromegaly) and in transgenic animal models is characterized by significant structural and functional changes in the kidney. In the human a direct relationship has been noted between the activity of the GH/IGF-1 axis and renal hypertrophy, microalbuminuria, and glomerulosclerosis. Conversely, states of GH deficiency or deficiency or inhibition of GH receptor (GHR) activity confer a protective effect against DN. The glomerular podocyte plays a central and critical role in the structural and functional integrity of the glomerular filtration barrier and maintenance of normal renal function. Recent studies have revealed that the glomerular podocyte is a target of GH action and that GH's actions on the podocyte could be detrimental to the structure and function of the podocyte. These results provide a novel mechanism for GH's role in the pathogenesis of DN and offer the possibility of targeting the GH/IGF-1 axis for the prevention and treatment of DN.

With the increased acceptance of glycated hemoglobin measurement as the test of choice for the diagnosis and detection of diabetes, doubts which surround the use of the oral glucose tolerance test (OGTT) in detecting disturbances in glucose levels have become even more apparent. Metabolically, there are still arguments to use the OGTT. Epidemiological studies though, have not always supported the efficacy of the OGTT when used for screening in obese patients. In our opinion, current evidence suggests an additive value of the OGTT, its main advantage being the ability to detect stages of pre-diabetes more accurately than HbA1c and the ability to investigate postprandial glucose levels in a physiological way.

A systematic review was conducted to evaluate the effectiveness of initiating insulin treatment with insulin glargine or insulin detemir for type 2 diabetes in a routine clinical practice setting. Medline, EMBASE and Cochrane literature databases were searched to identify published “real world” reports. Studies were included in the review if they reported the following; insulin dose, change in HbA1c, change in body weight and hypoglycemic events. In routine practice, decreases in HbA1c associated with insulin glargine and insulin detemir were variable and ranged between approximately -0.3% to -1.5% depending on prior treatment, but switching to insulin analogs was associated with less weight gain than previously reported. Compared with data reported in published trials, hypoglycemic event rates associated with basal analog insulin use in clinical practice were lower in patients initiating insulin and comparable in patients using basal-bolus regimens. Most patients were treated with low doses of insulin analog administered as once daily injections. In routine clinical practice most patients stopped concomitant use of sulfonylureas when initiating insulin analogs and it is likely that this together with the lower dose of insulin influenced outcomes. Nevertheless, despite initiating insulin therapy, it was also apparent that for many patients in routine clinical practice attainment of glycemic goals remains elusive.