Podocyte detachment and reduced endothelial cell fenestration and relationships between these features and the classic structural changes of diabetic nephropathy have not been described in patients with type 2 diabetes. Here we studied these relationships in 37 Pima Indians with type 2 diabetes of whom 11 had normal albuminuria, 16 had microalbuminuria, and 10 had macroalbuminuria. Biopsies from ten kidney donors (not Americans Indians) showed almost undetectable (0.03%) podocyte detachment and 43.5% endothelial cell fenestration. In patients with type 2 diabetes, by comparison, the mean percentage of podocyte detachment was significantly higher in macroalbuminuria (1.48%) than in normal albuminuria (0.41%) or microalbuminuria (0.37%). Podocyte detachment correlated significantly with podocyte number per glomerulus and albuminuria. The mean percentage of endothelial cell fenestration was significantly lower in macroalbuminuria (19.3%) than in normal (27.4%) or microalbuminuria (27.2%) and correlated significantly with glomerular basement membrane thickness, albuminuria, fractional mesangial area, and the glomerular filtration rate (iothalamate clearance). Podocyte detachment and diminished endothelial cell fenestration were not correlated, but were related to classic lesions of diabetic nephropathy. Thus, our findings confirm the important role these injuries play in the development and progression of kidney disease in type 2 diabetes, just as they do in type 1 diabetes. Whether podocyte detachment creates conduits for proteins to escape the glomerular circulation and reduced endothelial fenestration lowers glomerular hydraulic permeability requires further study.

OBJECTIVE -The purpose of this study was to investigate the effect of periodontitis on development of overt nephropathy, defined as macroalbuminuria, and end-stage renal disease (ESRD) in type 2 diabetes. RESEARCH DESIGN AND METHODS -Individuals residing in the Gila River IndianCommunity aged Ն25 years with type 2 diabetes, one or more periodontal examination, estimated glomerular filtration rate Ն60 ml/min per 1.73 m 2 , and no macroalbuminuria (urinary albumin-to-creatinine ratio Ն300 mg/g) were identified. Periodontitis was classified as none/ mild, moderate, severe, or edentulous using number of teeth and alveolar bone score. Subjects were followed to development of macroalbuminuria or ESRD, defined as onset of renal replacement therapy or death attributed to diabetic nephropathy.RESULTS -Of the 529 individuals, 107 (20%) had none/mild periodontitis, 200 (38%) had moderate periodontitis, 117 (22%) had severe periodontitis, and 105 (20%) were edentulous at baseline. During follow-up of up to 22 years, 193 individuals developed macroalbuminuria and 68 developed ESRD. Age-and sex-adjusted incidence of macroalbuminuria and ESRD increased with severity of periodontitis. After adjustment for age, sex, diabetes duration, BMI, and smoking in a proportional hazards model, the incidences of macroalbuminuria were 2.0, 2.1, and 2.6 times as high in individuals with moderate or severe periodontitis or those who were edentulous, respectively, compared with those with none/mild periodontitis (P ϭ 0.01). Incidences of ESRD in individuals with moderate or severe periodontitis or in those who were edentulous were 2.3, 3.5, and 4.9 times as high, respectively, compared with those with none/mild periodontitis (P ϭ 0.02).CONCLUSIONS -Periodontitis predicts development of overt nephropathy and ESRD in individuals with type 2 diabetes. Whether treatment of periodontitis will reduce the risk of diabetic kidney disease remains to be determined. Diabetes Care 30:306 -311, 2007P eriodontitis is a common infection of the periodontal tissues (1) and a major cause of tooth loss in adults (2,3). The most prevalent form is chronic periodontitis (1). Individuals with diabetes are at increased risk of developing periodontitis, and, once established, periodontitis is more severe in people with diabetes (3-6). Poor glycemic control hastens the progression of periodontitis and, in turn, periodontitis appears to further impair glycemic control (6 -8).Periodontitis predicts cardiovascular disease risk (9) and deaths from diabetic kidney disease and cardiovascular disease in individuals with type 2 diabetes (10). However, the relationship between periodontitis and diabetic kidney disease has not been fully explored. Among nonobese individuals with type 2 diabetes in Japan, IgG titers for Porphyromonas gingivalis (a periodontal pathogen) were correlated with the urinary albumin-to-creatinine ratio (ACR), although analyses were not adjusted for confounding factors (11). In the Atherosclerosis Risk in Communities (ARIC) Study, a largely nondiabetic p...

Murine models are valuable instruments in defining the pathogenesis of diabetic nephropathy (DN), but they only partially recapitulate disease manifestations of human DN, limiting their utility. To define the molecular similarities and differences between human and murine DN, we performed a cross-species comparison of glomerular transcriptional networks. Glomerular gene expression was profiled in patients with early type 2 DN and in three mouse models (streptozotocin DBA/2, C57BLKS db/db, and eNOS-deficient C57BLKS db/db mice). Species-specific transcriptional networks were generated and compared with a novel network-matching algorithm. Three shared human–mouse cross-species glomerular transcriptional networks containing 143 (Human-DBA STZ), 97 (Human-BKS db/db), and 162 (Human-BKS eNOS−/− db/db) gene nodes were generated. Shared nodes across all networks reflected established pathogenic mechanisms of diabetes complications, such as elements of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and vascular endothelial growth factor receptor (VEGFR) signaling pathways. In addition, novel pathways not previously associated with DN and cross-species gene nodes and pathways unique to each of the human–mouse networks were discovered. The human–mouse shared glomerular transcriptional networks will assist DN researchers in selecting mouse models most relevant to the human disease process of interest. Moreover, they will allow identification of new pathways shared between mice and humans.