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Insulin Signalling to the Kidney in Health and Desease

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Clinical Science (2013) 124, 351370 (Printed in Great Britain) doi: 10.1042/CS20120378

Insulin signalling to the kidney in health and diseaseLorna J. HALE and Richard J. M. COWARDAcademic and Childrens Renal Unit, University of Bristol, Learning and Research, Southmead Hospital, Bristol BS10 5NB, U.K.

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AbstractNinety-one years ago insulin was discovered, which was one of the most important medical discoveries in the past century, transforming the lives of millions of diabetic patients. Initially insulin was considered only important for rapid control of blood glucose by its action on a restricted number of tissues; however, it has now become clear that this hormone controls an array of cellular processes in many different tissues. The present review will focus on the role of insulin in the kidney in health and disease.Key words: diabetes, diabetic nephropathy, insulin, intracellular signalling, kidney, metabolic syndrome

OVERVIEW OF CELLULAR INSULIN SIGNALLINGThe role of insulin in the human body has been an active subject of interest since the discovery of insulin in 1921 by Banting, Best, Collip and Macleod. The critical importance of this nding was recognized by the Nobel Committee in 1923 when they awarded Banting and Macleod the Nobel Prize in Physiology or Medicine [1] just 2 years after their discovery. In the 50 years that followed the effects of insulin were intensely studied and revealed its glucose-controlling effects focusing on the liver, muscle and adipose tissue [2]. Insulin is a highly potent physiological anabolic hormone that promotes the synthesis and storage of lipids, carbohydrates and proteins, while also inhibiting their degradation and release back into the circulation. In mammals insulin is the main hormone controlling blood glucose; it achieves this by stimulating glucose inux and metabolism in muscles and adipocytes, and by inhibiting gluconeogenesis by the liver. These tissues have always been considered the classically insulin-sensitive organs of the body. However, insulin has the ability to modify the expression and/or activity of an assortment of enzymes and transport systems in a wide variety of cell types [3], as the present review will describe.

INSULIN AND IGF (INSULIN-LIKE GROWTH FACTOR) RECEPTORSWhen discussing the receptors that insulin can signal through it is important to consider another closely related collection of hormones, namely the IGF family. The reason for this is that the IGF hormones, IGF-I and IGF-II, have structural similarity to insulin and their major functional receptor, IGF-IR (IGF-I receptor) [4,5], is also structurally similar to the IR (insulin receptor). The signicance of this is that insulin can signal through the IGFIR and likewise IGF-I/-II can signal via the IR, although with differing afnities. Indeed, it is even more complicated than this as hybrid receptors are formed, by combinations of the IR and IGF-IR, through which all of the hormones can signal but with differing afnities (Table 1). Insulin has the greatest afnity for the IR, so the rest of the present review will predominantly focus on this receptor. The IR in humans is located on chromosome 19 and is encoded by a gene containing 22 exons and 21 introns spanning 120 kb [6,7]. It is a heterotetrameric receptor consisting of two and two subunits [8], which are linked by disulde bonds in a --- conguration (Figure 1). The subunits are extracellular and have the insulin-binding domain, whereas the subunits

Clinical Science

, , Abbreviations: BK channel, large-conductance Ca2 + -activated K + channel; BP blood pressure; CAP Cbl-associated protein; DM, diabetes mellitus; DN, diabetic nephropathy; DOK, downstream of kinase; ECM, extracellular matrix; eNOS, endothelial NO synthase; ERK, extracellular-signal-regulated kinase; ESRD, end-stage renal disease; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GFB, glomerular ltration barrier; GFR, glomerular ltration rate; GLUT, glucose transporter; GEnC, glomerular endothelial cell; Grb2, growth-factor-receptor-bound protein 2; IGF, insulin-like growth factor; IGF-IR, IGF-I receptor; IL, interleukin; IR, insulin receptor; IRS, insulin receptor substrate; ksp, kidney-specic; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MPGN, membranoproliferative glomerulonephritis; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; OMIM, Online Mendelian Inheritance in Man ; PH, pleckstrin homology; PI3K phosphoinositide 3-kinase; podIRKO mouse, podocyte-specic IR-decient transgenic mouse; PPAR , peroxisome-proliferator-activated receptor ; PTB, phosphotyrosine-binding; Raptor, regulatory associated protein of mTOR; RBF, renal blood ow; SGK1, serum- and glucocorticoid-induced protein kinase 1; SH2, Src homology 2; SOS, Son of Sevenless; TRPC, transient receptor potential cation channel; TSC, tuberous sclerosis complex. Correspondence: Dr Richard Coward (email [email protected]).

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L. J. Hale and R. J. M. Coward

Table 1

Receptor subtypes of the insulin/IGF system in mammals Variable assembly of receptors showing the primary ligand-binding afnities for each. Ligand(s) Receptor Homotetramers IR-B/IR-B IR-A/IR-A IGF-IR/IGF-IR Heterotetramers (hybrids) IR-B/IR-A IR-B/IGF-IR IR-A/IGF-IR HIR-AB HR-B HR-A Insulin and IGF-II IGF-I IGF-I, IGF-II and insulin IGF-II IR-B IR-A IGF-IR Insulin Insulin and IGF-II IGF-I and IGF-II IGF-II IGF-I IGF-I Insulin Name Level of afnity . . . High-level Mid-level Low-level

have three compartmental domains: extracellular, transmembrane and cytosolic domains. Tyrosine residues in the cytosolic domain of subunits are involved in signal transduction and are autophosphorylated when insulin binds to the receptor or by exogenous tyrosine kinase activity [8]. There is a further level of complexity within the IR as it exists in two different isoforms, A and B, which are formed due to the inclusion or exclusion of exon 11 of the IR gene [911]. IR-A lacks exon 11, whereas IR-B includes it. IR-A is widely expressed throughout the body but is importantly up-regulated during prenatal development and when cells become cancerous [7]. IR-B is expressed largely in the classically insulin-sensitive tissues of liver, skeletal muscle and adipose tissue. Interestingly IR-B is also expressed in the kidney [12,13]. The IR isoforms dimerize and can form either pure or hybrid receptors with each other or the IGF-IR. The receptor make-up dictates the afnity of the cell for insulin and/or the IGF ligands, as the different receptors have differing afnities for each of these molecules (Table 1). It should also be noted that IRs are not solely located in glucoseregulating insulin target tissues, but in many other tissue types, suggesting other functional roles of insulin signalling in multiple biological systems distinct from glucose homoeostasis. The IR and IGF-IR mediate the actions of IGF-I, IGF-II and insulin. The IGF-IR shares a high degree of homology with the IR [14,15] (Figure 1). It is therefore unsurprising that insulin is capable of activating the IGF-IR and vice versa. IGF-I has the greatest afnity for the IGF-IR, followed by IGF-II, with insulin having a 500-fold lower afnity in comparison with its primary ligands [14].

CELLULAR INSULIN SIGNALLING PATHWAYSThe majority of work in this eld has been performed on adipocytes, liver and skeletal muscle, as these are crucial for postprandial glucose regulation in response to insulin. The insulin signal transduction pathway is highly conserved and responsible for the regulation of a number of aspects of cellular physiology, most notable of which is the metabolic effects of glucose uptake and its utilization within the cell. Following a meal, increased levels of insulin encourage enhanced glucose uptake, metabolism and storage within muscle and adipose cells

[16]. Insulin levels rapidly increase approximately 10-fold after a meal from a basal level of approximately 50 pmol to 600 pmol [17]. GLUTs (glucose transporters) are energy-independent and allow glucose to enter or leave the cell, passively down a concentration gradient, when they are incorporated into the cell membrane. The classic insulin-responsive glucose transporter is GLUT4 [18], which translocates from a cytoplasmic vesicular pool to the plasma membrane in response to insulin. This is the signature molecule of rapidly insulin-sensitive cells that absorb glucose. However, there is also robust evidence that GLUT1 [19] can also translocate in a similar manner from an intracellular pool to the plasma membrane and rapidly increase its plasma membrane concentration in response to insulin. GLUT1 is also a constitutional transporter in many cells [20]. Here it sits at the plasma membrane of cells continuously and allows a constant delivery of glucose for cellular function. The IR differs from many other receptor tyrosine kinases in that, instead of recruiting downstream effector molecules to its phosphorylated cytoplasmic domains, when activated it phosphorylates a number of scaffolding proteins which then in turn are responsible for recruiting various downstream effector proteins [21]. A number of intracellular substrates have been discovered, including the IRS (insulin receptor substrate) family (IRS1 IRS4), IRS5/DOK4 (downstream of kinase 4), IRS/DOK5, Gab1, Cbl, APS [adaptor protein with PH (pleckstrin homology) and SH2 (Src homology 2) domains] and Shc isoforms, and SIRP (signal regulatory protein) family members [22,23]. The best characterized have been the IRS family of proteins [24]. IRS proteins do not possess intrinsic catalytic activities, and are instead composed of multiple interaction domains and phosphorylation motifs. Four IRS proteins have been identied (IRS1IRS4), with IRS1 and IRS2 being the most widely expressed. E