BackgroundDiabetic nephropathy (DNP) is a common complication of type 1 and type 2 diabetes mellitus and the most common cause of kidney failure. While DNP manifests with albuminuria and diabetic glomerulopathy, its progression correlates best with tubular epithelial degeneration (TED) and interstitial fibrosis. However, mechanisms leading to TED in DNP remain poorly understood.Methods and FindingsWe found that expression of scavenger receptor CD36 coincided with proximal tubular epithelial cell (PTEC) apoptosis and TED specifically in human DNP. High glucose stimulated cell surface expression of CD36 in PTECs. CD36 expression was necessary and sufficient to mediate PTEC apoptosis induced by glycated albumins (AGE-BSA and CML-BSA) and free fatty acid palmitate through sequential activation of src kinase, and proapoptotic p38 MAPK and caspase 3. In contrast, paucity of expression of CD36 in PTECs in diabetic mice with diabetic glomerulopathy was associated with normal tubular epithelium and the absence of tubular apoptosis. Mouse PTECs lacked CD36 and were resistant to AGE-BSA-induced apoptosis. Recombinant expression of CD36 in mouse PTECs conferred susceptibility to AGE-BSA-induced apoptosis.ConclusionOur findings suggest a novel role for CD36 as an essential mediator of proximal tubular apoptosis in human DNP. Because CD36 expression was induced by glucose in PTECs, and because increased CD36 mediated AGE-BSA-, CML-BSA-, and palmitate-induced PTEC apoptosis, we propose a two-step metabolic hit model for TED, a hallmark of progression in DNP.
To describe gene expression changes that characterize the development of diabetic nephropathy, we performed microarray and phenotype analysis on kidneys from db/db mice (a model of type 2 diabetes), streptozotocininduced diabetic C57BL/6J mice (a model of type 1 diabetes), and nondiabetic controls. Statistical comparisons were implemented based on phenotypic outcome characteristics of the animals. We used weighted votebased supervised analytical methods to find genes whose expression can classify samples based on the presence or absence of mesangial matrix expansion, the best indicator for the development of end-stage renal disease in humans. We identified hydroxysteroid dehydrogenase-3 isotype 4 and osteopontin as lead classifier genes in relation to the mesangial matrix expansion phenotype. We used the expression levels of these genes in the kidney to classify a separate group of animals for the absence or presence of diabetic glomerulopathy with a high degree of precision. Immunohistochemical analysis of murine and human diabetic kidney samples showed that both markers were expressed in podocytes in the glomeruli and followed regulation similar to that observed in the microarray. The application of phenotype-based statistical modeling approaches has led to the identification of new markers for the development of diabetic kidney disease. Diabetes 53: 784 -794, 2004
We previously described a gene, Ipl (Tssc3), that is expressed selectively from the maternal allele in placenta, yolk sac, and fetal liver and that maps within the imprinted domain of mouse distal Chromosome (Chr) 7/human Chr 11p15.5 (Hum Mol Genet 6, 2021, 1997). Ipl is similar to TDAG51, a gene that is involved in FAS/CD95 expression. Here we describe another gene, Tih1 (TDAG/Ipl homologue 1), with equivalent sequence similarity to Ipl. Structural prediction indicates that the products of these three genes share a central motif resembling a pleckstrin-homology (PH) domain, and TIH1 protein has weak sequence similarity to the PH-domain protein SEC7/CYTOHESIN. Like Ipl, Tih1 is a small gene with a single small intron. Tih1 maps to distal mouse Chr 1 and human Chr 1q31, chromosomal regions that have not shown evidence for imprinting and, in contrast to Ipl, Tih1 is expressed equally from both parental alleles. Ipl, Tih1, and TDAG51 have overlapping but distinct patterns of expression. Tih1 and TDAG51 are expressed in multiple fetal and adult tissues. In contrast, during early mouse development Ipl mRNA and protein are highly specific for two tissues involved in maternal/fetal exchange: visceral endoderm of the yolk sac and labyrinthine trophoblast of the placenta. These findings highlight the dominance of chromosomal context over gene structure in some examples of parental imprinting and extend previous evidence for placenta-specific expression of imprinted genes. The data also define a new subfamily of PH domain genes.
Altered calcium [Ca2+] transients of vascular smooth muscle cells to vasoconstrictors may contribute to altered regulation of blood flow in diabetes. We postulated that diabetes-induced transforming growth factor (TGF)-beta production contributes to impaired ANG II response of vascular smooth muscle cells in macrovessels and microvessels. Aortic vascular smooth muscle cells isolated from diabetic rats exhibited markedly impaired ANG II-induced cytosolic calcium [Ca2+] signal that was completely restored by pretreatment with anti-TGF-beta antibodies. Similar findings were noted in microvascular smooth muscle cells isolated from preglomerular vessels and cultured in high glucose. The impact of diabetes on [Ca2+] transients was replicated by addition of TGF-beta1 and -beta2 isoforms to aortic smooth muscle cells in culture and diabetic cells had enhanced production of TGF-beta2. In the in vivo condition, TGF-beta1 was increased in diabetic glomeruli, whereas TGF-beta2 was increased in diabetic aorta. The characteristic increase in glomerular filtration surface area found in diabetic rats was prevented by treatment with anti-TGF-beta antibodies, and impaired ANG II-induced aortic ring contraction in diabetic rats was completely restored by anti-TGF-beta antibodies. Impaired vascular dysfunction may be partly due to decreased inositol 1,4,5-trisphosphate receptor (IP3R), as reduced type I IP3R expression was found in diabetic aorta and restored by anti-TGF-beta antibodies. We conclude that TGF-beta plays an important role in the vascular dysfunction of early diabetes by inhibiting calcium transients in vascular smooth muscle cells.
Abstract. Insight into the molecular mechanisms that underlie the origin and progression of diabetic nephropathy remains limited in part because conventional research tools have restricted investigators to focus on single genes or isolated pathways. Microarray technologies provide opportunities for evaluating genetic factors and environmental effects at a genomic scale during the pathogenesis of diabetic nephropathy. Despite the enormous power of the microarray technology, there are several pitfalls that need to be considered. This article discusses conceptual, practical, statistical, and logistical considerations for the use of microarrays in studies of experimental and human diabetic renal disease. New knowledge in this field will facilitate new approaches for molecular diagnosis and drug discovery.Diabetes is the most common metabolic disorder with an estimated worldwide prevalence between 1 and 5%. One of the most severe complications of diabetes is the development of diabetic nephropathy (DNP). Diabetic renal disease is the single most common cause of ESRD in the United States, accounting for 43% of new cases (1,2). Furthermore, diabetic ESRD is associated with a poor life expectancy.Clinical studies have identified risk factors that correlate with the development of ESRD in diabetes. The presence of microalbuminuria, hypertension, and poor glycemic control are the most important risk factors (3). It is clear, however, that poor glycemic control alone is not sufficient for the development of this complication. Long-term observational studies show that a maximum of 35% of patients develop nephropathy, irrespective of glycemic control (4). This is in contrast to retinopathy, for which the prevalence continues to rise with the duration of diabetes. Family studies showed that among patients with type 1 diabetes, when one sibling develops nephropathy, the other one has a fourfold increased risk of nephropathy compared with the sibling of a patient without nephropathy (5). These observations have clearly established the importance of genetic risk factors in the development of DNP.
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