Impaired insulin action, combined with its insufficient secretion, can cause diabetes. In a surprising extension of this notion, decreased insulin action in the kidney's podocyte cells may contribute to renal complications in diabetes.
The hormone insulin is best known for regulating glucose and fat metabolism in skeletal muscle, fat tissue and the liver. Impaired insulin action in these tissues is central to the development of type 2 diabetes, which can be debilitating or even fatal, owing to kidney failure or cardiovascular complications. During the past decade or so, responses to insulin have been identified in other cell types, where some of its effects are completely different from those regulating metabolism. Writing in Cell Metabolism, Welsh et al.1 show that, in mice, loss of insulin action in podocytes — a specialized type of kidney cell — can cause changes in kidney structure and function that resemble the renal complications of human diabetes known as diabetic nephropathy.
One of the kidney's main functions is to regulate water and salt balance in the body. To this end, the kidney performs ultrafiltration of blood plasma: every day, some 70 litres of filtrate pass through the kidney's collecting ducts, while plasma macromolecules such as albumin are retained. Plasma filtration takes place through loops of capillaries in microscopic structures called renal glomeruli. These capillaries are covered by podocytes, which are epithelial cells that coat the entire capillary surface with the foot-like processes that give them their name. The filtration barrier consists of a single layer of endothelial cells — the cell type that forms the inner lining of all blood vessels — separated from the podocytes by a basal membrane.
One of the earliest abnormalities in the development of diabetic nephropathy is shortening of podocyte foot processes, which contributes to the breakdown of the glomerular filtration barrier, thereby allowing albumin and other macromolecules to escape into the urine. Albumin loss in the urine and other renal abnormalities, which in some cases progress to kidney failure, also frequently occur in patients with metabolic syndrome — a common condition, associated with obesity and impaired insulin action. Drugs that decrease blood glucose, lower blood pressure or inhibit the actions of the hormone angiotensin can delay, but not eliminate, the onset of diabetic nephropathy.
To relay its signal from the bloodstream to a cell's interior, insulin binds to receptors on the cell surface. Welsh et al.1 used mice in which the gene encoding the insulin receptor was deleted specifically from podocytes. At birth, kidney appearance in these animals was normal. At five weeks of age, however, they began to show excretion of albumin in the urine, shortening of the podocyte foot processes, increased deposition of components of the basal membrane, and a higher frequency of programmed podocyte death through apoptosis. Some animals even developed shrunken kidneys with prevalent scar tissue similar in appearance to the kidneys of humans with late-stage diabetic nephropathy.
These findings, however, are not just notable for their striking similarity to the pathology of diabetic nephropathy in humans. Welsh and colleagues' mice also showed mild worsening of kidney function. This observation is intriguing because, in the most commonly studied rodent model of diabetes, destruction of insulin-producing cells with the drug streptozotocin causes no significant change in kidney function, despite resulting in microscopic kidney abnormalities and albumin excretion in the urine2.
Welsh et al. also report that insulin can reorganize the actin cytoskeleton in podocytes maintained in culture. This phenomenon resembles the actin remodelling seen when insulin causes translocation of glucose-transport proteins to the cell surface in fat or skeletal muscle cells3. Exactly how regulation of the cytoskeleton affects both podocyte foot processes and the filtration barrier requires more detailed investigation.
Remodelling of the actin cytoskeleton also does not explain the increased apoptosis of podocytes lacking insulin receptors. In this regard, the observation4 that insulin enhances the expression of the protein vascular endothelial growth factor (VEGF) — a crucial survival factor as well as a regulator of blood-vessel formation — might be of relevance. Podocytes are the main source of VEGF in the kidney: mice lacking VEGF specifically in podocytes show partial loss of all major cell types in the glomerulus, including podocytes5,6. Moreover, VEGF expression is reduced in tissues such as heart muscle in animals with diabetes7. Insulin can also prevent apoptosis by other mechanisms8,9, including inactivation of the transcription factor FoxO and inhibition of caspase-9, a signalling molecule that promotes apoptosis.
Whether insulin signalling to other cell types in the glomerulus is essential for maintenance of the filtration barrier is not known. Dysfunction of endothelial cells in the systemic circulation is associated with the initiation and progress of diabetic nephropathy, and endothelial cells respond to insulin by changing the production of factors that regulate blood-vessel tone and by decreasing oxidant production and increasing levels of antioxidant enzymes10.
It also remains to be seen whether podocytes, or other renal cells, are insulin resistant in diabetes and metabolic syndrome in other animal models and in humans. It could be that some cell types or insulin-signalling pathways are more susceptible to insulin resistance than others. For example, insulin increases sodium transport in the kidney's tubular cells, but this aspect of its function is not affected in diabetes11. To understand whether insulin resistance in other renal cells contributes to diabetic nephropathy, researchers must study normal insulin action in kidney cells; whether these cells develop insulin resistance in metabolic syndrome and/or in diabetes; and what causes impaired insulin signalling.
With its focus on insulin resistance in glomerular cells, Welsh and co-workers' paper1 helps to establish that diabetic nephropathy — the leading cause of chronic kidney disease in developed countries — may result from the impaired actions of survival factors such as insulin, in addition to the deleterious effects of increased concentrations of glucose, angiotensin and other factors. This may provide the rationale for evaluating existing insulin-sensitizing drugs, as well as those under development, for their ability to improve insulin action in the kidney. It may also prove fruitful to develop insulin analogues that preferentially activate insulin-stimulated mechanisms in podocytes and other kidney cells. It is to be hoped that these strategies will provide further ways to decrease the risk of diabetic nephropathy.
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