aldose reductase in the etiology of diabetic complications: 2. nephropathy

Aldose Reductase in the Etiology of Diabetic Complications: 2. Nephropathy

Donald Stribling, BSc, PhD*

Frank M. Armstrong, BSc, MRCPt

Heather E. Harrison, BSc, PhD$

*Bioscience II, j-Medical Research Department, $ Medical Affairs Department, ICI

Pharmaceuticals, Mereside, Alderley Park, Maccles field, Cheshire SK10 4TG, England

Reprint requests: H. E. Harrison, PhD, International Medical Information, Med- ical Affairs Department, ICI Pharmaceu- ticals, Mereside. Alderley Park, Maccles- field, Cheshire SK10 4TG, England. Submitted for publication in April 1988; accepted in revised form in July 1988.

ABSTRACT

The progression of diabetic nephropathy can be arrested by an improvement in diabetic control. High glucose concentrations increase the flux through the aidose reductase pathway, and it has been proposed that this may contribute to renal damage. Aidose reductase is present in both the giomeruius and the renal tubule. Biochemical changes associated with increased sorbitoi production have been demonstrated in animal models, including myo-inositoi depletion, reduced Na+-KC ATPase activity, and activation of the pentose phosphate and giucuro- nate-xyiose pathways. Selective inhibition of aidose reductase reverses these biochemical changes and prevents some of the structural and functional abnormalities in diabetic rats. The potential beneficial effects of aidose reductase inhibitors on diabetic kidney disease in man are at present being investigated. (The Journal of Diabetic Complications, 3;2:70-76, 1969.)

INTRODUCTION

The first article in this series discussed the background to the hypothesis that excess activity of the aldose reductase pathway during hyperglycemia could contribute to the development of diabetic complications. Although the hypothesis was originally derived from exper- iments on sugar cataract in alloxan diabetic rats, subsequent information has led to the proposal that a similar process could be involved in the initiation or exacerbation of pathologic changes in other tissues affected by the complications of diabetes.

Diabetes is one of the commonest causes of renal impairment in adults. End-stage renal failure develops in 3040% of insulin- dependent and 5-10% of non-insulin-dependent diabetics.’ The dis-

ease process in insulin-dependent diabetics has been described in five stages by Mogensen.2 .Diabetic renal invotvement consists of a triad of renal hyperfunction, urinary albumin/protein excretion, and diastolic

hypertension, evident to a variable degree at each stage.

Stages 1 and 11 Early in the course of diabetic renal involvement, abnormalities of renal hemodynamics occur. These include glomerular hyperfiltration, elevation of renal plasma flow, nephromegaly,3 and possibly abnormal renal hemodynamic responses to an oral protein load.4

SlagI? Ill As diabetic renal disease progresses, the excretion of albumin in the urine increases. Stage III is defined as microalbuminuria or incipient nephropathy.sVibertPand, subsequently, other investigators7 have shown that the presence of microalbuminuria is prognostic of nephropathy in insulin-dependent diabetics, and of nephropathy and early death in non-insulin-dependent diabeticsa,

SiaQt?S IV and V These stages are characterized by increasing albumin excretion and decreasing glomerular protein selectivity, failing renal function, and hypertension. Gross proteinuria, which is variably defined as “Albustix”-positive urine or an albumin excretion rate of >500 mg per 24 hours or 200 pg per minute, establishes the diagnosis of diabetic nephropathy and heralds a progressive decline in renal function. Glomerular filtration rate (GFR) falls by approximately 10 ml/min/year, although there is considerable interpatient variation.lO Within 7 years

70

ALDOSEREDUCTASEANDDIABETICNEPHROPATHY

of developing diabetic nephropathy, most diabetic patients

will require renal replacement therapy. The mortality associated with proteinuria in insulin dependent diabetics is considerable, with a 7 year survival of only 51%.” Recent studies have linked proteinuriatoother cardiovascular risk factors12,13 and the high mortality to cardiovascular disease.14 The early disease process is not as well characterized in non-insulin-dependent diabetics who may present with Stage IV or V disease.

Structural changes occur in the kidney in diabetes; these include nephromegaly, increases in glomerular volume, thickening of glomerular basement membrane, deposition of basement membrane-like material in the mesangium, and an increase in mesangial volume. Early studies by Osterby’s showed that thickening of glomerular capillary basement membrane was not present at diagnosis of diabetes, but occurred after 2-3 years. The increase in capillary basement membrane was found to precede mesangial expansion, but the rates of development of the two types of lesions correlated after 3.5-5 years of insulin-dependent diabetes.16

More recently, attempts have been made to relate the structural abnormalities to the functional changes in the diabetic kidney. A raised GFR in newly diag- nosed insulin-dependent diabetics has been shown to correlate with an increased glomerular capillary surface area,17 and Gundersen and Osterbyla have demonstrated a relationship between the percentage of oc- cluded glomeruli and serum creatinine concentration in patients with renal insufficiency. A study by Mauer and associatesi showed that clinical manifestations of diabetic nephropathy, such as albuminuria, hypertension, and decreased GFR, correlated poorly, or not at all, with glomerular basement membrane thickening, but were

strongly associated with mesangial expansion. A number of therapeutic approaches have been shown

to affect some of the early signs of diabetic nephropathy. A pathologically elevated GFR may be reduced by indomethacin,20 although the evidence is controversial,21 or intensified insulin therapy.22 These treatments also produce acute or sustained reductions in microalbuminuria, as does a thromboxane synthetase inhibitor,23 a protein-restricted diet,z4 or a hypotensive dose of an ACE inhibitor.zs The long-term benefits of a reduction in a supranormal GFR or microalbuminuria are unclear, although there is evidence to suggest that early glomerular hyperfiltration may be related to late renal disease.26 Continuous subcutaneous insulin infusion (CSII) has been suggested as having a possible effect on the progression of microalbuminuria to diabetic nephropathy.27 Evidence of the effects of glycemic control on proteinuria is, however, conflicting.28.29

Control of hypertension has been shown to have beneficial effects on the progression of diabetic renal disease. Diastolic blood pressure is usually elevated in incipient nephropathy,30 and arterial blood pressure increases as renal function declines and may contribute to progressive renal failure.31 Studies have shown that aggressive treatment of hypertension slows the rate of decline of renal function.32,33 This effect may be independent of the antihypertensive agent used, although it has recently been suggested that ACF inhibitors may have additive effects with other antihypertensive drugs.34

None of the therapeutic maneuvers described has been conclusively shown to prevent the progression of

diabetic renal disease. When proteinuria develops, irre-

versible damage is probably already present; interven- tion at an earlier, potentially reversible, phase therefore seems more appropriate. The recognition of the triad of renal hyperfunction, urinary albumin excretion, and diastolic hypertension as markers of early diabetic renal involvement may help to identify patients who are “at risk” for subsequent development of diabetic nephropathy, but the current vogue for treating diabetics who have

minimally elevated diastolic blood pressure (particularly those with microalbuminuria) requires long-term critical evaluation.

The mechanisms responsible for diabetic renal damage are unknown, although the observation that im- proved metabolic control may prevent the progression of diabetic renal involvement has focused attention on the consequences of hyperglycemia. Hyperglycemia results in increased sorbitol production through the aldose reductase pathway in tissues that are independent of insulin. In this article, the possible role of the aldose reductase pathway in the development of diabetic renal disease is considered.

PRESENCE AND LOCALIZATION OF ALDOSE REDUCTASE IN THE KIDNEY

As discussed in the introductory article of this series, aldehyde reductase (ALRl) and aldose reductase (ALR2) belong to a class of aldo-keto reductases that utilize

NADPH. The enzymes have overlapping substrate specificity and close sequence homology, but have a differen- tial tissue distribution. 35 ALRl, which uses glucuronate as the preferred substrate, and ALR2 have been identified in the kidney. 36 Crude fresh homogenates of rat kidney catalyze NADPH-dependent reduction of glyc- eraldehyde, which is a substrate for both ALRI and ALR237; substrate specificity of the crude homogenate suggests that the predominant enzyme is ALRl, not ALR2. Using specific antisera for ALR2, McDonald38 has shown that rat kidney homogenate contains significant amounts of ALR2, although the levels are some 70% lower than those measured in either nerve or lens. This does not allow, however, for the possibility that aldose reductase is localized within specific cell types in the kidney.

While these results are consistent with the presence of significant amounts of ALR2 in the kidney, results from immunohistochemical studies on the localization of ALRI and ALR2 have been confusing. In the origi- nal work by Kern and Engerman ALR2 was reported to be present in the renal medulla and papilla (collecting tubules, loop of Henle, interstitial cells, and papillary epithelium). However, ALR2 was demonstrated in the renal cortex, which includes the glomeruli, and is the primary site of morphologic changes in diabetes. Ludvig- son and Sorensen40 similarly identified ALR2 activity in the tubules, collecting ducts, and papilla, but also found that, depending on the method of fixation used, ALR2 was present in the cortex, specifically in the podocytes of the glomeruli.

In the most recent study, Terubayashi41 used antibod- ies raised against both purified ALRl and ALR2 and con-

72 STRIBLING, ARMSTRONG, AND HARRISON

eluded that ALRl was present throughout most struc- tures of the kidney, while ALRP was present only in the proximal tubule. Neither enzyme was present in the glomerulus. This could be a reflection of either the low total levels of enzyme or loss of enzyme during fixation.

With current knowledge of the close sequence homology of ALA1 and ALR2 and possible variant enzymes and isoenzymes in different tissues, antisera need to be checked for specificity against the enzymes present in the tissue under study. This, combined with the prob- lems of enzyme elution during fixation, makes it difficult to draw firm conclusions from the studies to date. How- ever, studies have shown accumulation of sorbitol and galactito142V43 in the kidneys of rats with experimental diabetes or rats fed galactose. This finding indicates the presence of functional amounts of ALR2 approaching the levels found in nerve and other tissues. Pretreatment of animals with ponalrestat (“Statil”‘, ICI 128,436, “Pro- diax”t MK 538), which has been shown to be from 100 to 150 times more selective for ALRP than ALR1,44 reduces polyol accumulation in both models, which again indicates the presence of ALR2.

The physiologic role of aldose reductase is unclear, but it has been suggested that sorbitol acts as a coun- terosmolyte in the renal tubule.45 This suggestion is sup- ported by the observation that in cultured tubular endothelial cells, aldose reductase activity is induced by high concentrations of NaCI.

BIOCHEMICAL CONSEQUENCES OF THE PRESENCE OF ALDOSE REDUCTASE IN DIABETES

The complex structure of the kidney and the apparently uneven distribution of ALR2 complicate the interpreta- tion of increased polyol concentration in whole tissue. Separate assay of the renal cortex, however, shows a fourfold increase in sorbitol levels in diabetic rats compared with nondiabetic animals,46 while glomeruli isolated from the kidney of diabetic rats contain from 4 to 10 times the amount of sorbitol found in glomeruli of normal controls.43 isolated glomeruli from normal animals, when incubated in media containing high levels of glucose43 or galactose (unpublished results), accu- mulate significant amounts of the corresponding polyol. Furthermore, both cultured mesangial cells4’ and kidney epithelial cell.@ can be shown to synthesize poly- 01s. These findings, together with the high sensitivity of mesangial cells to ponalrestat, further confirm the presence of ALR2.

Beyer-Mears and colleagues43 demonstrated that sorbitol levels in glomeruli were greater at 6 and 9 weeks after induction of diabetes than in nondiabetic rats. Sor- bitol levels were lower, however, at 9 weeks than at 6 weeks, perhaps suggesting a progressive disruption of cell permeability. Glomerular myo-inositol was lower after 9 weeks of diabetes than in nondiabetic animals. Co-

“‘Statil” is a trademark, the property of Imperial Chemical In- dustries PLC. t”Prodiax” is a trademark, the property of Merck 8 Co., Rahway, New Jersey.

hen and others49 confirmed the decrease in glomerular myo-inOsito( leVelS and demonstrated an associated reduction in ouabain-sensitive Na+-K+ ATPase in rats made diabetic less than 3 weeks previously. Incuba- tion of glomeruli in media containing high levels of glucose inhibits the active sodium-dependent uptake of myo-inositol.50 These results suggest a mechanism similar to that proposed for sciatic nerve by Greene and others,5’ in which sorbitol accumulation is linked with the depletion of myo-inositol and a consequent reduction in Nat-K+ ATPase. In rats with diabetes for more than 6 weeks, however, Cohen and associate@* found that the activity of Na+-K+ ATPase returned to normal in untreated diabetic rats while myo-inositol levels remained depressed. These findings cast doubt on a causal relationship, although the increase in Na+-K+ ATPase may merely reflect an adaptive response to polyuria in diabetic rats.

Treatment of diabetic rats with the aldose reductase inhibitor, sorbinil (CP 45,634), has been shown to prevent the depletion of myo-inositol and the increase in Na+-K+ ATPase activity in glomeruli in acute diabetes.52 The effects on Naf-Kf ATPase may not be related to the inhibition of aldose reductase, however, because Cohen and Klepser53 have found that sorbinil binds specifically to isolated glomeruli, while others have shown that the hydantoin inhibitors activate renal Naf-K+ ATPase di- rectly by binding at the low affinity ATP binding site; this property is not shared by the acidic aldose reductase inhibitors such as ponalrestat (“Statil”, ICI 128,436, MK 538) or tolrestat (“Alredase”$, AY 27,773).54

A spectrum of other biochemical changes, associated with an apparent activation of the pentose phosphate and glucuronate-xylose pathways and increased synthesis of glycogen, has been demonstrated in the kidneys of diabetic rats.55 The metabolite changes reflect an induction of hexokinase, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase. and phosphoglucomutase. Flux through the pentose phosphate pathway is reduced by ponalrestat treatment,56 possibly reflecting a reduced demand for NADPH sup- ply for the sorbitol pathway, while levels of glucose- 6-phosphate and glycogen are not affected, indicating that these are a direct consequence of hyperglycemia. Lactate levels are also increased in the kidneys of diabetic rats. This could be the result of increased gly- colytic activity arising from the increased availabil- ity of glucoseS-phosphate, or possibly from further metabolism of fructose via fructose-l-phosphate which bypasses the normal controls at phosphofructokinase. Although glucose-&phosphate levels are unchanged by ponalrestat treatment, lactate levels are significantly reduced, suggesting that at least part of the increase in lactate results from excess activity of the aldose reductase pathway.

In untreated diabetic rats, UDP-gluCOSe, a critical pre- cursor of basement membrane synthesis, increases by 25%, and this increase is attenuated by treatment with

$“Alredase” is a trademark, the property of Ayerst Laboratories.

ALDOSE REDUCTASE AND DIABETIC NEPHROPATHY

POLYOL PATHWAY)

NON-ENLYMIC GLYCOSYlATtON+- OF PROTEINS

gucoset , 7~ sorbito$~ fn~cto$

‘1 ‘, I

,’

t- mdmfes an mcmxe m the concentrahon oi a metabahte or fhe actrvrfy oi a pathway ,n dmbetes.

rndrcafes Ihat the rncrease can be mhrbiled by a” aldose reducfase rnh,bttor

FIG 1 Effect of diabetes and aldose reductase inhibitors on the pathways for glucose metabolism in the kidney.

ponalrestat56; this is consistent with reduced synthesis

of basement membrane. The effects of diabetes and aldose reductase inhibitors

upon pathways of glucose metabolism in the kidney are shown in Figure 1.

FUNCTIONAL AND STRUCTURAL CHANGES IN THE DIABETIC KIDNEY

In the rat, renal hypertrophy develops rapidly after induction of diabetes and is followed by hyperplasia. In- terpretation of these changes is complicated by the dra- matic increase in urine volume in uncontrolled diabetes. Furthermore, streptozotocin itself is nephrotoxic, caus- ing tubular damage, and could contribute to some of the morphologic changes. The impact of increased polyol accumulation can be separated from the effects of streptozotocin and polyuria by studying renal hypertrophy in galactose-fed rats. Rats fed a 50% galactose diet for 25 days have a reduced body weight, but display an increased absolute and relative kidney weight associated with an increased fluid content and renal mass. Both effects are inhibited by sorbinil ,s7 indicating that they are consequent on the activity of the aldose reductase pathway. However, the osmotic effects of galactose feeding

are more intense than those resulting from diabetes. In streptozotocin (STZ) diabetic rats, treatment with ponalrestat had no significant effect on the initial hypertrophy and hyperplasiaand had only a smal! effect on kidney size as a percentage of body weight over 6 months of diabetes. By contrast, the changes can be largely prevented by insulin administration (unpublished results). This suggests that the predominant effect on renal mass is due to the effects of hyperglycemia and polyuria, rather than either streptozotocin or sorbitol accumulation.

After 6 to 12 months of diabetes, there is a marked increase in staining with periodic acid Schiff reagent (PAS) in the rat kidney. This is associated with both an increased deposition of basement membrane material, resulting in some cases in the formation of nodules, and a change in staining characteristics, possibly reflecting an altered composition.

Treatment with ponalrestat from the time of induction of diabetes had a partial effect on the PAS +ve staining in kidney, possibly reflecting a decrease in basement membrane material (unpublished results). There is considerable controversy over whether treatment with an aldose reductase inhibitor prevents glomerular capillary basement membrane thickening in diabetic rats. At best, treatment with these agents achieves a partial effect in streptozotocin diabetic rats, whereas insulin treatment achieves complete normalization.58.60

Although urinary excretion of protein is not sim- ply a reflection of a size-selective permeability barrier, proteinuria increases progressively after induction of diabetes with streptozotocin. Administration of aldose reductase inhibitors, from the time of induction of diabetes, reduces protein excretion; this is associated with a decrease in albumin excretion.60,61 Some of the

changes in urinary excretion could be the consequence of streptozotocin administration but, in BB Wistar rats, urinary concentrations of albumin and N-acetyl-B-D- glucosaminidase increase progressively, and this increase can be prevented by treatment with epalrestat at a dose that causes a 50% reduction in total kidney sorbitol.62

Tilton” has demonstrated that renal blood flow, GFR, albumin clearance per gram of liver, and total albumin excretion increase in rats 6 weeks after the administration of streptozotocin. Treatment from the induction of diabetes with aldose reductase inhibitors prevents these early changes, indicating a primary role for sorbitol accumulation. A similar effect in reducing GFR was reported by Goldfarb and colleagues.64

The mechanism by which sorbitol accumulation might cause these fundamental alterations in renal hemodynamics is unclear, but Kikkawa65 has shown that isolated glomeruli incubated in media containing high concentrations of glucose show an abnormal contractile response to angiotensin II. Angiotensin receptors are located on both afferent and efferent arterioles and on mesangial cells within the glomerulus. Aldose reductase is generally present in capillary endothelial cells, but has not specifically been located in these arterioles. However, as previously discussed, mesangial cells contain high levels of aldose reductase as well as contractile elements.47 The mesangial cell plays a critical role in de- termining perfusion of the glomerular tuft. All the functional and structural changes in the kidney could stem from a breakdown in this control system. In support of this hypothesis, treatment of diabetic rats with ACE inhibitors has been shown to prevent the development of glomerular capillary hypertension and to retard the development of albuminuria and glomerulosclerosis.66

The structural and functional changes that occur in the kidney in diabetes, and the effects of aldose reductase inhibitors on these changes, are summarized in Table 1.


TABLE 1 Effects of Diabetes and Atdose Reductase lnhibltors on Kidney Structure and Function in Experimental Animals

Ellectr 01 Diabetes Effects 01 ARla

In Dlabetk Anlmrlr

SlWClU~d Renal hypertrophy Little effect Glomerular caDillarv Reduction”,59

BM thickening ’ Increased PAS+ve

Functlonrl staining

Proteinuria (increased urinary albumin and N-acetyl-B-D-glucosaminidase)

Increased renal blood flow Prevention62 Increased GFR Prevention62

Reduction

CONCLUSIONS AND CLINICAL IMPLICATIONS

It is clear from biochemical studies that aldose reductase is present in the kidney and that its presence results in a wide spectrum of primary and secondary biochemical changes in diabetes. From the structural and functional studies, it would appear that excess activity of the aldose reductase pathway results in a number of changes in diabetic animals that mirror those seen in diabetic nephropathy in man. The renal abnormalities in diabetic animals can be distinguished from the nephrotoxic effects of streptozotocin, and high concentrations of aldose reductase in mesangial cells, which show early changes in diabetes, indicate that this may be the primary site of damage. This is consistent with the observed effects of ACE inhibition.

Although many of the changes in diabetic animals can be duplicated in galactosemic animals, Kern and Engermane’ have reported that kidneys taken from chronically galactosemic dogs that developed retinopa- thy showed only some of the renal changes associated with diabetes. In particular, the accumulation of basement membrane material was considerably reduced, although there were some small increases in glomerular basement membrane width and the amount of trapped plasma protein. Galactosemia does not achieve the full spectrum of biochemical and functional changes resulting from metabolism of sorbitol. Aldose reductase inhibitors can achieve only a partial correction of the accumulation of PAS +ve material in the kidney of diabetic rats, while insulin treatment is fully ef- fective, implying that an additional process contributes to the development of morphologic changes in hyperglycemia; this could be non-enzymatic glycosylation and crosslinking of the extracellular matrix as proposed by Brownlee. The identification of aminoguanidine as a model compound that prevents the crosslinking of Amadori product+ should permit the definition of the functional significance of this process.

The majority of the animal studies have concentrated on the prevention of changes in the kidney following the induction of diabetes. Sochor and others56 demonstrated, however, that a similar reversal of biochemical changes could be achieved when treatment with ponalrestat was instituted after 21 days of diabetes. Simi-

larly, Beyer-Mears70 showed that treatment of BE3 Wistar rats with sorbinil reversed proteinuria after 4 weeks of diabetes, while Watanabe62 showed that effects on albumin excretion and basement membrane thickness were achieved by treatment over a period 4-8 weeks after development of diabetes in the BB Wistar rat. Nevertheless, these are short time scales compared with the protracted development of the clinical syndrome.

Although the animal models reflect many of the changes seen in the development of diabetic nephropathy, none so far has been shown to result in progressive renal failure. It is impossible, therefore, to determine whether treatment with an aldose reductase inhibitor would influence this process. The lesions modeled are those common to a wide group of diabetics, many of whom do not progress to gross proteinuria. The nature of the effects achieved by aldose reductase inhibitors in animal models, and clinical experience in the manage- ment of progressive renal failure, would indicate, however, that early interventions (before GFR begins to decline and gross proteinuria develops) would be the most likely to achieve benefit. If aldose reductase inhibitors can be shown to have a beneficial effect on the indices of incipient nephropathy, then their use will depend on a fuller understanding of the natural history of the disease and improvements in its early detection.

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aldose reductase in the etiology of diabetic complications: 2. nephropathy

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