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Vol. 14. Núm. 3.Junio 1994
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Cell biology of diabetic nephropathy.
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E. N. WARDIE
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NEFROLOGIA. Val. XIV. Núm. 3. 1994 EDITORIAL Cell biology of Diabetic Nephropathy E. N. Wardle, MD, MRCP Oxford. Reino Unido Introduction 40 % of patients with juvenile insulin dependent diabetes mellitus (IDDM) develop nephropathy within 10-20 years of diagnosis 1, 20 % of middle aged, noninsulin dependent diabetes mellitus (NIDM) patients a r e f o u n d t o have n e p h r o p a t h y o n l y 5-10 years after the initial diagnosis 2 . Generally the patients with early proteinuria are those who have had poor glucose control 3, a slightly higher blood pressure (135: 85 mm Hg) and more marked retinopathy. They are those who soon have an increase of their GFR above normal and so they have hyperfiltration. They tend also to have a higher cholesterol, a higher LDL and VLDL, and elevation of their plasma fibrinogen 4. After 5-10 years of diabetes we might detect microalbuminuria, which means an albumin excretion rate of 20-200 micrograms/minute in an overnight urine, or 30-300 mg/24 hrs in a complete collection. Then after another 5-10 years they will develop albumin stick positive proteinuria. The clinical sequence of the development of diabetic nephropathy was described in detail by Castiglioni and Savazzi 5. When biopsies are obtained from diabetic patients, the changes that are typical are ' the hyalinosis of the afferent and efferent arterioles of the glomeruli 2 , the thickening of the basement membranes of the glomerular capillaries 6 , and3 the increased volume of mesangial cells leading to an increase in volume of glomeruli. Once the expansion of the mesangium is more than 37 % of the glomerular volume, there is pressure on the capillaries with loss of filtration surface 7, so that thereafter there is functional renal impairment. Ultimately there is closure and obsolence of glomeruli, called glomerulosclerosis. Those patients with severe glomerular lesions have hypertension and reduced creatinine clearance, and there is renal interstitial fibrosis. There is evidente that this fibrosis develops concurrently with the increased fractional mesangial volume 8. Clomerular Capillary Hipertension and Hyperfiltration In rats that are made diabetic by means of streptorotocin and kept alive by injections of insulin there is a decreased resistance of the afferent arterioles, so that there will be increased pressure in the glomerular capillaries and there is hyper-filtration 9 , which is determined by the increase in plasma flow. The factors that determine hyperfiltration have been discussed by Bank 10 . Hyperglycaemia is a first consideration 11 but so is a high protein intake 12. A very high glucose (20 mM) inhibits cytosolic calcium signaling in cultured mesangial or vascular smooth muscle cells 11b.Hence there is vasodilatation. Sodium intake is also relevant. During hyperglycaemia induced osmotic flow, there is increased reabsorption of sodium in the proximal tubules 13 . In subjects who are using insulin, insulin is known to increase sodium reabsorption in the tubules 14. The pituitary of diabetic patients secretes large pulses of growth hormone, possibly as a result of raised glucose in the CSF, and growth hormone increases GFR and renal blood flow 15 by the intermediary of insulin growth factor IGF-1 16 , In any case there is increased formation of nitric oxide vasodilator in the afferent arterioles in diabetes 17. The hyperglycaemia also results in production of vasodilator prostaglandins in the afferent artérioles 18 . This production of prostaglandins seems to depend on polyol formation, because it is arrested 19. when an aldose reductase inhibitor is used Hyperglycaemia determines also an increased production of thromboxanes at the vascular pole of diabetic kidneys and thus an increased tone in the efferent arterioles 10 . Indeed one knows that urinary thromboxane excretion is increased 10, and that proteinuria is ameliorated in animals given thromboxane synthetase inhibitor 20 Yet another consideration is that hyperglycaemia leads to formation of excess diacylglycerol withi cells and thus there is activation 257 E. N. WARDLE of protein kinase C. Excess protein kinase C is known to mediate vascular permeability of the endothelium of blood vessels 21, In fact it mediates down-regulation of thromboxane receptors in diabetic glomeruli and mesangial cells 22, Angiotensin II receptors are likewise downregulated. In all this will explain the predominant vasodilatation in the afferent arterioles and so the hyperfiltration. The data in humans indicates some relation between early hyperfiltration and the development of diabetic renal disease. Thus in one study of children a GFR in excess of 125 ml/min 1.73 m2 conferred a predictive value for nephropathy of 53 % 23 . Yet one must note that in that study half of the hyperfiltering subjects did not develop nephropathy during the period of follow-up. Thus hyperfiltration is not a highly sensitive predictive parameter. N I D D M patients also show hyperfiltration 2 4 . Itis common in Pima Indians 25. It has been suggested that the patients who progress to diabetic nephropathy are those with a family predisposition to hypertension 26. Hypertension will raise intracapillary pressures and worsen proteinuria. In some populations genetic susceptibility to essential hypertension can be linked to increased erythrocyte sodium-lithium counter-transport. There is a similar link with diabetic nephropathy 27. However one must emphasize that this does not apply in all populations that have been studied 28 . There has to be a metabolic component to the hypertrophy that stems from the hyperglycaemia. Thus it has now been demonstrated that in the kidneys of diabetic rats there is an increase of glucosylceramide, a glycosphingolipid precursor. Furthermore an inhibitor of glucosyl-ceramide prevents the renal hypertrophy 39 . Vascular Changes in Diabetes Hyalinosis of blood vessels is recognised as an adverse feature. It means that the vessel walls are permeable to molecules as large as fibrinogen. It implies that glomerulosclerosis will develop 40. When it occurs leakiness of the postglomerular peritubular capiIlaries leads to protein accumulation in the interstit i u m of the kidneys 4 1 T h a t will lead to renal . interstitial fibrosis. The process is probably facilitated by iron that comes from transferrin in the urine of diabetics 42. What causes increased endothelial cell permeability in diabetes? Firstly metabolism of glucose to diacylglycerol that mediates the formation of excess protein kinase C has been mentioned 21. Secondly a role for conversion of glucose to sorbito1 via aldose reductase enzyme is probable, because the inhibitor sorbinil can reduce vascular permeability 43 . Thirdly there is a definite role for lipid peroxides, which arise when there is free radical formation linked to nonenzymic glucosylation of proteins 4 4 - 4 5 . The freeradicals arise from auto-oxidation reactions of sugars and sugar adducts to proteins and by auto-oxidation of unsaturated lipids adjacent to altered membrane prot e i n s . Monocytes of diabetics often produce superoxide anions and thus hydrogen peroxide 4 6 . Polymorphonuclear leucocytes in serum that is high in cholesterol also form superoxide anions 47. It is usual for the low density lipoproteins of diabetics to become oxidised 48 . Apart from that one can gauge free radical activity in diabetic rats by their expiration of pentane 4 9 , and one canmeasure plasma lipid peroxides and lipid peroxidation of kidneys in diabetic rats 50, In human studies severa1 groups have now related lipid peroxides in plasma 51 (measured by thethiobarbituric acid reaction) to endothelial cell damage as shown by a raised plasma von Willebrand factor. The patients with raised plasma malonyldialdehyde (indicative of lipid peroxides) and raised plasma von Willebrand factor were also those who had microalbuminuria 52-54. Furthermore patients with raised plas. ma MDA were those with tubular damage as shown by increased excretion of NAG, N-acetyl-glucosaminidase, in their urine 54. When sought in the correct Hypertrophy of the Kidneys Soon after the onset of diabetes the size of the kidneys increase. All the glomeruli and their nephrons hypertrophy 29. In the rat this hypertrophy precedes the increase of GFR 3 0 . The finding of increasedprotein kinase C activity in the glomeruli is relevant to growth 31. Both hyperglycaemia and the growth factors work via pkC activation. It has been shown that the action of EGF, epidermal growth factor, works through the intermediary of increased protein kinase C activity 32. EGF is produced in the distal tubules and ascending loops of Henle 33, There is increased excretion of EGF in the urine of streptozotocin diabetic rats 3 4 , The effects of growth hormone are known to be mediated by IGF-1 and this is anabolic and it is involved in hypertrophy of diabetic kidneys 35. In short term studies the somatostatin analogue, octreotide, which suppresses growth hormone secretion, stops the early renal hypertrophy of diabetic rats 3 6 . Yet in the longterm it does not 37. Hyperglycaemia stimulates production of TGFbeta in cultured proximal tubules 38 .It is therefore possible that it could contribute to hypertrophy of the tubules, albeit how TGFbeta behaves depends on the phase of development. 258 E. N. WARDLE manner, marked evidence of tubular damage will be found in many diabetics 55,56. Oxidised LDL has altered properties 57 that are pertinent to atherogenesis 58. Oxidised LDL is chemotactic for monocytes and it is taken up by macrophages in arterial walls to cause their cholesterol enrichment and foam cell formation. Oxidised LDL causes platelet aggregation. It stops the action of nitric oxide and so it can promote vasoconstriction in small arterioles. Oxidised LDL can be cytotoxic for endothelial cells. In lesser doses it causes the expression of «tissue factor» thromboplastin on endothelial cells 59, so that there is a thrombotic tendency in small arterioles. It also prevents activation of protein C and so it thwarts protective fibrinolysis. The severe atheroma that many diabetics develop has implications for kidney function. For example platelet aggregates forming in the aorta will be swept into the glomeruli to cause lesions like focal segmental sclerosis 60. Also many diabetics do have renal artery stenoses. Recognition of this fact is necessary before the prescription of ACE inhibitors. Non-enzymatic glucosylation of proteins produces ACEP, advanced glycosylation end-products 45. They accumulate in the tissues of diabetics 61 and will undoubtedly play a role in nephropathy. Mesangial cells express AGEP receptors 6 2 and when stimulated by AGEP they form basement membrane proteins 63. AGEP have oxidising potential 64, and when they accumulate in blood, as they do in terminal renal failu6 5 they encourage procoagulant change on the endothelial cells 66, both directly and via release of cytokines like ll-1 and TNFa 67. Glycosaminoglycans and Collagen There is poor synthesis of heparan sulphate proteoglycans by the renal glomeruli in diabetes mellitus 68. There is a genetic factor involved in different strains of rats 71, and it has also been suggested that the varying liability to diabetic vascular disease in humans 69 m i g h t also d e p e n d on some factor like this. Hyperglycaemia also stops proteoglycan synthesis by mesangial cells 7 0 . When there is poor diabetic control there is inhibition of the N-acetyl heparan deacetylase enzyme that is required for heparan sulphate proteoglycan synthesis. Furthermore there is loss of heparan sulphates in the urine at the onset of diabetes in rats 72. When biopsies from human diabetic nephropathy were examined, a marked reduction in reactivity to anti-heparan sulphate proteoglycan antibodies was observed, but one has to acknowledge that these were cases of quite advanced disease 73. The importance of the heparan sulphates is that the 260 negative charges of their sulphate groupings on endothelial cells, and in the basement membranes of the glomeruli and on the mesangial cells, repel negatively charged albumin molecules, so that their filtration is prevented. So it would seem that loss of heparan sulphates at such an early stage in diabetes 74 could account for the onset of micro-albuminuria. Indeed Gambaro et al. 75 have show.n that, when streptozotocin diabetic rats are given injections of either low MW heparin or dermatan sulphate glycosaminoglycan, there was inhibition of mesangial cell expansion and thickening of the glomerular basement membranes was reduced. The heparan sulphates of the basement membrane are essential for the integrated binding of the other components like the type IV collagen and laminin. Another factor that contributes to proteinuria must also be the poor synthesis in diabetes 76 of the negatively charged sialoproteins that line the slit pores between the epithelial cells. The basement membrane width expands by about 30 % during the first 5 years of diabetes and by the time of clinical nephropathy its width has doubled 6 . Not only is there loss of negative charges 73 but the closely woven structure must be disorganised, perhaps by the addition of glucoadducts in the process of non-enzymic glucosylation 61,77-79, surely by the effect of ACE products causing collagen browning 80 , and surely as a result of the loss of heparan sulphate proteoglycans 81. When in an experimental situation a m i n o g u a n i d i n e is used to decrease AGE products 8 2 , the proteinuria is reduced 83 . A high ambient glucose (30 mM) increases the synthesis of type IV collagen by cultured endothelial, mesangial and epithelial cells 84-85. Undoubtedly the ability of high glucose to drive protein kinase C may explain this 86. However one should also be aware that lipid peroxidation enhances the synthesis of type I V collagen Also it can be shown in vivo that thromboxanes play a role, because when thromboxane synthase inhibitors are used basement membrane thickening and mesangial matrix expansion is reduced 87,88. The basic fact that high ambient glucose c a u s e s increases messenger RNA for type IV collagen 89,90 has now been verified by many groups. Likewise proximal tubules that are exposed to glucose will synthesise type IV collagen of tubular basement membranes 91, It is reported that sorbinil prevents the biosynthesis 91. Clearly the altered structure of the GBM explains the albuminuria and the loss of charge selectivity that can now be measured by study of the clearance of IgG/lgG4 92,93. As can be shown by dextran clearances, there is initially no increase of pore size at a time when there is substantial loss of albumin and IgG, E. N. WARDLE We know from histology that glomerulosclerosis (mesangial sclerosis) will ultimately develop and that follows increasing deposition of fibronectin and type IV collagen. High glucose leads to loss of proteoglycans 111 and it promotes formation of fibronectin and collagen 9 7 - 9 8 , albeit one set of studies showed that over a long time high glucose suppresses collagen The Altered Mesangia of Glomeruli of Diabetics production 111. That might be due to ascorbic acid deThe feature that is so typical of diabetes is the early pletion, since that is well recognised in diabetes. Certainly it seems that hyperlipidaemia will mediamesangial cell expansion that is followed years later by mesangial sclerosis 5 , 7 . Thus the picture differs t e glomerulosclerosis, as in other situations 112. from the glomerulonephritides in which one often exImmunohistochemical studies of the localisation of apolipoproteins in glomeruli has shown that fixation pects to see mesangial cell proliferation that is cauof apolipoprotein B with apoE gives rise to more glosed by growth factors 96. By now one can list various merulosclerosis and interstitial scarring 1 1 3 . experimental observations that explain why the mesangial cells do not proliferate. 1) A high ambient What more does one need to know? Since mice glucose (20 mM) inhibits mesangial cell proliferation, transgenic for bovine growth hormone1 1 4 develop although it does promote fibronectin synthesis 9 7 . 2) mesangial cell proliferation by 4 weeks, mesangial Although a high glucose increases protein kinase C in sclerosis by 20 weeks and glomerulosclerosis by 36 mesangial cells 9 8 and thus formation of extracellular weeks, what are the mediators of the response? matrix fibronectin, laminin and type IV collagen, Presumably PDGF autocrine production in glomeruli is involved at the early stage 110. Since TGFbeta is the high glucose also inhibits cytosolic calcium signa9 9 . Hence the cells will tend to be relaxed and Iling mediator of glomerulosclerosis in most situations, one has to assume that this is also the case in diabespread out rather than contractile. 3) Non-enzymatic tic nephropathy 110, Indeed it does seem that high gluglucosylation and formation of ACE products causes mesangial expansion and inhibition of mesangial cell cose stimulates autocrine production of TGFbeta by mesangial cells 1 0 4 . p r o l i f e r a t i o n 4) On account of the aldose reductase content of the mesangia, exposure to high glucose Furthermore the release of TGFbeta stops mesanw i l l result in formation of polyols 101 and there will be gial cell proliferation but increases the deposition of mesangial matrix 115. a reduction of the myoinositol of the cells 102. 5) When there is a high glucose, prostaglandin production by mesangial CelIs is increased 103 Prostaglandins Final Synopsis inhibit cell oroliferation 9 6 . Potential high glucose induced mesangial cell proliferation is inhibced also by By now it has been shown in rats with diabetic nephropathy and in humans that TGFbeta values are transforming growth factor beta 1 0 4 . 6) Highglucose can inhibit the cell proliferative effect of ICF-1 105 . 7) elevated in the glomeruli 115 . Thisis a clear indication Low density lipoproteins at a concentration of only that TGFbeta mediates glomerulosclerosis. 10 g/ml stimulate proliferation of mesangial cells and Secondly Cohen and Ziyadeh 117 have examined yet at a level of 1 0 0 - 5 0 0 g/ml, as would be the case the effects of glycosylated proteins on glomerular mesangial cells. They have shown that glycosylated in any hyperlipidaemia, there is inhibition 106. Such proteins (i) stop proliferation of mesangial cells, and LDL will stimulate superoxide production by mesangial cells and thus may become oxidised 107 . 8) (ii) stimulate the mesangial cells to transcribe the geOxidised LDL reduces release of growth factors from nes for type IV collagen. So growth of mesangial cells is inhibited, as was recorded by Crowley et macrophage like cells 1 0 8 . Oxidised LDL bind very well to mesangial cells and inhibit their proliferation al.100, and type IV collagen production occurs in dia109. betic glomeruli. One should note that when glycated at concentrations as low as 10-25 g/ml Although these observations make good biochemiproteins are taken up by mesangial cells, there is incal sense, they are mainly based on in vitro studies. tracellular production of hydrogen peroxide 64,118 When RNA messengers are looked at in the early staWe do know that lipid peroxidation is a stimulus to ges of diabetes in Sprague-Dawley rats those for collagen production 6 6 , In fact Cohen and Ziyadeh TNFalpha, basic fibroblast growth factor and PDGF-B used glycated serum proteins that had no cross-links chain and for transforming growth factor beta are inand showed no AGE fluorescente, whereas Crowley creased 110. Indeed their levels are reduced by insulin et al. 1 0 0 specifically used fluorescent cross-linked AGE products. Thus either product can influente the therapy 110. Nevertheless rats are not as hyperlipaemic as man might be. genes for collagen. 262 but pore size is increased later. It is relevant to note that glycated albumin readily leaks through the glomeruli and it is not reabsorbed by the proximal tubules 94. In any case.there is often proximal tubule dysfunction as shown by lysozymuria 95. CELL BIOLOGY OF DIABETIC NEPHROPATHY Thirdly there is more information on the contraversial topic of whether or not nitric oxide production by endothelium is increased o decreased in diabetes. The answer is that NO production can be increased or decreased depending on the vascular bed. Nitric oxide production is increased in the afferent arteriales of diabetic glomeruli and thus this is a factor that explains vasodilatation and hyperfiltration. On the other hand it has been shown that carbamvlcholine induced cyclic GMP is decreased within isolated diabetic glomeruli in parallel with hyperglycaemia induced increases of protein kinase C 119. 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