Altered Transcapillary Escape of Albumin and Microalbuminuria Reflects Two Different Pathogenetic Mechanisms

Abstract

We studied the following in normo-and microalbuminuric hypertensive type 2 diabetic patients: 1) transcapillary escape rate of albumin (TERalb) and 2) expression of mRNA slit diaphragm and podocyte proteins in renal biopsies. Normoalbuminuric subjects had renal cancer, and kidney biopsy was performed during surgery. TERalb was evaluated by clearance of 125 Ialbumin. Real-time PCR of mRNA slit diaphragm was measured in kidney specimens. Albumin excretion rate (AER) was by definition lower in normoalbuminuric subjects than in microalbuminuric subjects with typical diabetic glomerulopathy (group 1), in microalbuminuric subjects with normal or near-normal glomerular structure (group 2), and in microalbuminuric subjects with atypical diabetic nephropathy (group 3). This classification was based on light microscopy analysis of renal tissue. TERalb (%/h) was similar in normoalbuminuric and microalbuminuric group 1, 2, and 3 diabetic patients (medians: 14.1 vs. 14.4 vs. 15.7 vs. 14.9, respectively) (ANOVA, NS). mRNA expression of slit diaphragm proteins CD2AP, FAT, Actn 4, NPHS1, and NPHS2 was higher in normoalbuminuric patients than in microalbuminuric patients (groups 1, 2, and 3) (ANOVA, P < 0.001). All diabetic patients had greater carotid artery intimal thickness than normal control subjects using ultrasound technique (ANOVA, P < 0.01). In conclusion, the present study suggests that microalbuminuria identifies a subgroup of hypertensive type 2 diabetic patients who have altered mRNA expression of slit diaphragm and podocyte proteins, even before glomerular structure shows abnormalities using light microscopy analysis. (1) suggested some years ago an interesting view to understanding the pathogenesis of albuminuria in diabetes, which has been usually cited as the Steno hypothesis and implies that albuminuria reflects a widespread vascular damage due to a generalized vascular dysfunction in the overall vascular bed. According to this hypothesis, albuminuria may be a marker of generalized disease in the vascular wall, either at endothelial or glomerular basement membrane (GBM) levels or both, although the precise reasons for this relationship are not completely understood.If the Steno hypothesis really does account for both the leakage of albumin at kidney level and an increased transport of albumin across microvascular capillaries in the overall body, one should predict that transvascular and urinary leakage of albumin are correlated throughout a gamut of pathological conditions both in type 1 and type 2 diabetic patients.However, this is not the case in previous reports both in type 2 diabetic patients and in nondiabetic atherosclerotic and hypertensive patients, in whom transvascular escape of albumin was similarly abnormal in normoalbuminuric and micro-/macroalbuminuric patients (2,3).Major attention has been paid in the last 30 years to the role of the GBM as the primary filter capable of maintaining albumin and large proteins into circulation (4). Because GBM is widespread throughout the entire vascular bed of ...

Increased Renal Arterial Resistance Predicts the Course of Renal Function in Type 2 Diabetes With Microalbuminuria

“…This has been demonstrated by Adler et al (29) and by our research group (11), who showed in microalbuminuria altered mRNA expression of several glomerular proteins.…”

“…The patterns of renal lesions in the 157 type 2 diabetic patients with hypertension and microalbuminuria were classified as described previously using light microscopy technique by A.S. and R.F. (4,11,25,26), who were unaware of the clinical features of the patients as follows. Category 1.…”

“…Moreover, it has been convincingly reported that tight blood pressure control, particularly using drugs that inhibit the renin angiotensin system, significantly delay the progression of renal damage in diabetic patients with incipient or advanced nephropathy (7)(8)(9)(10). Nevertheless, 15-20% of the diabetic patients still relentlessly develop ESRD, despite aggressive antihypertensive and hypoglycemic therapy (4,6,10,11).…”

Association analysis of podocyte slit diaphragm genes as candidates for diabetic nephropathy

“…Alpha actinin 4 is not a slit diaphragm protein per se, but is located in the vicinity of the slit diaphragm in the cytoskeleton of the podocyte foot process [5]. Interestingly, the alpha actinin 4 mRNA is underexpressed in the glomeruli of patients with microalbuminuria compared with patients with normal AER [10]. In addition, a combination of glucose and advanced glycation end-products reduced the expression of alpha actinin-4 at both the protein and the Table 1 c Patients homozygous for the minor allele (2/2) were compared with patients homozygous for the major allele (1/1) d The non-synonymous R229Q SNP in NPHS2 characterised by Tsukaguchi et al [13] was included mRNA level in podocytes in vitro [11].…”

Strain vessel hypothesis: a viewpoint for linkage of albuminuria and cerebro-cardiovascular risk

“…[21][22][23] It has been suggested that albuminuria not only reflects glomerular damage, but also is a sensitive indicator of generalized endothelial dysfunction and capillary vasculopathy that leads to penetration of atherosclerotic lipoproteins into the arterial walls. [24][25][26] Although albuminuria is associated with endothelial dysfunction in systemic circulation, 26 the mechanism for this association remains unclear.…”