Extracellular Matrix Proteins as Early Markers in Diabetic Nephropathy

Abstract

Summary: Basement membrane thickening and mesangial expansion characterize the renal involvement in diabetes mellitus and precede any symptoms of renal dysfunction, e. g., albuminuria and changes in glomerular filtration rate. Since the morphological changes can only be diagnosed by biopsy, this study was designed to investigate whether the urinary excretion of renal extracellular matrix proteins might reflect the morphological alterations.To specify the extent of renal involvement in diabetes, the patients, type I as well as type II diabetics, were classified according to their urinary albumin excretion: normal albumin excretion below 30 μg/min, microalbuminuria from 30 to 300 μg/min, and overt albuminuria above 200 μg/min. Laminin, collagen IV, and fibronectin, all intrinsic components of the renal extracellular matrix, were determined in serum and urine by radioimmunoassay or enzymelinked-immunosorbent-assay, respectively. The results are given as median values (x). Additionally, the urinary fragment pattern of fibronectin was analysed qualitatively by immunoblotting.Laminin concentrations in serum and in urine did not change in diabetics. Collagen IV decreased in serum of patients with increased albumin excretion (controls: χ = 255 μg/l, normoalbuminuric patients: χ = 56 μg/l J microalbuminuric patients: χ = 52 μg/l, and patients with overt albuminuria: χ = 70 μg/l; α < 0.01) and increased in urine (controls, normoalbuminuric and microalbuminuric patients: not detectable, patients with overt albuminuria: χ = 5 ng/12 h; α < 0.001). Fibronectin was elevated in serum (controls: χ = 355 mg/1; normoalbuminuric patients: χ = 640 mg/1, microalbuminuric patients: χ = 710 mg/1, and patients with overt albuminuria: χ = 630 mg/1; α < 0.0001) and in urine, even in patients with normal albumin excretion (controls: χ = 16.8 μg/12 h, normoalbuminuric patients: x= 121 μg/12h, microalbuminuric patients: x = 108μg/12h, patients with overt albuminuria: χ = 186 \ig/l2 h; α < 0.01). The urinary fragment pattern of fibronectin, consisting of two main bands of a relative molecular mass of M r 75000 and 45000, was not altered in controls and diabetics. Type I and type II diabetic patients did not show significant differences in any quantities tested.It was shown in this study that the determination of laminin and collagen IV in serum and urine gave no information exceeding the routinely used quantities of kidney function. But the renal fibronectin excretion was elevated before any functional changes occurred. It was concluded that this might be indicative of the early mesangial expansion in diabetes mellitus. The determination of urinary fibronectin could therefore probably serve as a more sensitive marker for renal involvement in diabetes mellitus than microalbuminuria or changes in glomerular filtration rate.

Effect of 17-Β Estradiol Supplementation on Reversion of Diabetic Renal Fibrosis

“…In the present study, diabetes for 8 weeks was associated with degenerative changes in the kidney as glomerular expansion, tubular dilatation and tubular cells vacuolations, mononuclear cell infiltration and significant increase of the amount collagen fibers in the glomeruli and tubular interstitium. This is in agreement with several previous studies (Jackle-Meyer et al, 1995;Ma et al, 2004;Mankhey et al, 2007). Longstanding diabetes for 16 weeks was asso-ciated with progressive damage of the kidney in the form of progressive glomerulosclerosis and tubulo-interstitial fibrosis, with mononuclear cells infiltration.…”

Effect of protopanaxadiol derivatives in high glucose-induced fibronectin expression in primary cultured rat mesangial cells: Role of mitogen-activated protein kinases and Akt

“…Mesangial cells play an important role in the development of diabetic nephropathy, such as the increase of mesangium expression which induces diabetic glomerulosclerosis (Mason and Wahab, 2003). Fibronectin is one of major proteins composing of extracellular matrix in glomerulus (Jackle-Meyer et al, 1995). This report suggest the possibility that fibronectin may be a target protein in the development of diabetic nephropathy.…”

Complement Cascade Proteins Correlate with Fibrosis and Inflammation in Early-Stage Type 1 Diabetic Kidney Disease in the Ins2Akita Mouse Model

“…The innate immune system (a member of which is the complement cascade) is one of the major driving factors in the inflammatory response in DKD [13]. The activation of the inflammatory response eventually leads to cell injury and development of kidney fibrosis [9,[16][17][18][19][20][21].…”

“…In DKD, hyperglycemia, advanced glycation end products (AGEs), high lipid levels, and increased oxidative stress damage renal cells, leading to increases in both pro-inflammatory signaling pathways and the complement cascade [12][13][14][15]. Eventually, the sustained chronic inflammation leads to an altered kidney structure and fibrosis [9,[16][17][18][19][20][21].…”