Structural And Functional Glomerular Alterations In Diabetes

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The first major change after the onset of diabetes is the increased volume of the whole kidney and the glomeruli [19]. These hypertrophical glomeruli have normal structural composition. After a few years the amount of glomerular matrix material is increased [1,3]. Biochemical determinations indicate an increased amount of collagen in the glomerular extracellular matrices [20]. More recently, an increase in collagen type VI in the glomerular matrix of diabetic patients has been documented [21]. On the basis of immunochemical measurement, it has become evident that the HSPG content of glomerular matrix is lower in diabetic patients [22] consistent with previous chemical analyses of the heparan sulfate chains [23,24]. These immunochemical measurements, although yielding reliable quantitative values, were performed with preparations of glomerular matrices which contain firstly, both the basement membrane and the mesangial matrix and secondly a mixture of glomeruli which may be affected to a variable degree. Therefore, immunohistochemical studies have been performed to distinguish the changes within the different compartments of the glomerulus and between the individual glomeruli.

These immunohistochemical studies, summarized in table 2, indicate that in diabetic kidneys with slight lesions only a minor increase in all basement membrane components was found except for HSPG. More pronounced diffuse glomerulosclerosis showed a further increase in basement membrane components, especially collagen IV a1,a2-chains in the expanded mesangial matrix. However, HSPG which was entirely absent from the enlarged matrix could only be observed in the periphery of the glomeruli. The staining of collagen IV a3,a4-chain showed a similar distribution as found for HSPG however, with intense staining of the thickened glomerular basement membrane [6]. To this stage of nephropathy the accumulation of excess matrix material can be attributed to quantitative changes of the components present in normal glomeruli. In contrast, pronounced nodular lesions exhibited a strong decrease of collagen IV a1,a2-chains, laminin, and HSPG, which were only detectable in the periphery of the noduli. Staining sequential sections with collagen VI antiserum or PAS revealed coincidence of both stainings indicating that the noduli consist mostly of collagen type VI [8]. Peripheral areas of these noduli were also positive for collagen III, which was not detected in earlier lesions. It appears that in diffuse glomerulosclerosis an increase in normal matrix components occurs while the nodular glomerulosclerosis is characterized by qualitative changes (table 2). Morphological and structural changes occurring in the interstitium, tubuli or glomerular arterioles are a concomitant of diabetic nephropathy [1].

Table 2. Changes of glomerular matrix composition in different stages of diabetic glomerulosclerosis (GS)*

Diffuse GS

Nodular GS

GBM

mesangium

GBM

mesangium

laminin

T

T

T

4

collagen IV

a1,a2-chain

T

T

T

4

a3,a4-chain

T

-

T

T

HSPG

U

4

-

fibronectin A+

-

n.d.

-

T

collagen III

-

-1)

-

T2)

collagen VI

4

T 3)

4

T T

T = increased; 4 = decreased; ^ = unchanged; - = not detectable; *see also [6-8]; n.d. = not determined; 1)traces in late diffuse GS; 2)only peripheral; 3)focally

T = increased; 4 = decreased; ^ = unchanged; - = not detectable; *see also [6-8]; n.d. = not determined; 1)traces in late diffuse GS; 2)only peripheral; 3)focally

In vivo and in vitro studies of collagen metabolism in glomeruli obtained from diabetic animals demonstrated that increased collagen deposition is caused by an increased synthesis and concomitant decreased degradation [20,25,26]. Fukui et al. [27] found an increased steady state mRNA levels of the collagen IV

a1-chain, laminin B1 and B2 and fibronectin while the collagen I a1-chain was unchanged in the kidneys of diabetic rats after one month of diabetes. The message for HSPG was decreased after induction of diabetes and increased steadily afterwards. The changes in mRNA levels, which preceded the glomerular matrix expansion could be prevented by normalisation of blood glucose by insulin treatment. Recent in situ hybridization studies revealed that mRNA transcript levels of a1(IV) collagen are increased more than twofold in glomerular and proximal tubular cells in long-term (12 months) diabetic rats [28]. In the glomerulum, mainly mesangial cells showed enhanced a1(IV) collagen expression. The a1(IV) collagen deposition in the mesangial matrix was similarly increased. Chronic treatment with a modified heparin preparation completely prevented the increased a1(IV) collagen deposition and expression and the overt albuminuria in diabetic rats. Taken together, these results indicate that the increased synthesis of collagen IV, laminin and fibronectin is the biochemical correlate of the expansion of the mesangial matrix and the thickening of glomerular basement membrane observed histologically. The occurrence of decreased degradation of matrix components has also been documented [26].

Extensive studies have shown that the changes in glomerular ultrastructure are closely associated with renal function [2,3]. Comparing the immunohistochemical findings with clinical data Nerlich et al. [7] found that the increase in the glomerular matrix components was consistently associated with impaired renal filter function. Late stage nodular glomerulosclerosis associated with decrease of all basement membrane components, and increase in collagen III and VI coincided with severe renal insufficiency. In all cases, even in early diffuse glomerulosclerosis, HSPG was decreased.

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