Increased glomerular cell (podocyte) apoptosis in rats with streptozotocin-induced diabetes mellitus: role in the development of diabetic glomerular disease

• Published in: Diabetologia Vol. 50; no. 12; pp. 2591 - 2599
• Main Authors: Menini, S, Iacobini, C, Oddi, G, Ricci, C, Simonelli, P, Fallucca, S, Grattarola, M, Pugliese, F, Pesce, C, Pugliese, G
• Format: Journal Article
• Language: English
• Published: Berlin Berlin/Heidelberg : Springer-Verlag 01.12.2007; Springer; Springer Nature B.V
• Subjects: Albuminuria - etiology; Animals; Apoptosis; Apoptosis - physiology; Biological and medical sciences; Blood Glucose - metabolism; Body Weight - physiology; Cell cycle; Cell Cycle - genetics; Cell death; Creatinine - blood; Cyclin-dependent kinases; Diabetes; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Diabetic glomerular disease; Diabetic Nephropathies - blood; Diabetic Nephropathies - etiology; Diabetic nephropathy; Disease; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genes, p53; Glomerular hypertrophy; Glomerular sclerosis; Glomerulonephritis; Hypotheses; Kidney Glomerulus - pathology; Kidney Glomerulus - physiology; Kinases; Laboratory animals; Male; Medical sciences; Mesangial expansion; Microfilament Proteins - metabolism; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; p21; p53; Podocytes; Podocytes - pathology; Podocytes - physiology; Proteins; Proteinuria; Proteinuria - etiology; Rats; Rats, Sprague-Dawley; Streptozocin; Synaptopodin; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Italy; Endocrinopathy; Glomerulonephritis; Glomerulosclerosis; Rat; p53 Protein; Podocytes; Kidney; p53; Synaptopodin; Glomerular sclerosis; Development; Streptozotocin; Kidney disease; Glomerular hypertrophy; Urinary system disease; Mesangial cell; Diabetes mellitus; Rodentia; Apoptosis,Diabetic glomerular disease; p21; Renal glomerulus; Podocyte; Vertebrata; Mammalia; Urinary system; Cell death; Animal; Mesangial expansion; Apoptosis; Hypertrophy; Proteinuria
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-007-0821-y

Aims/hypothesis Podocyte loss by apoptosis, in addition to favouring progression of established diabetic nephropathy, has been recently indicated as an early phenomenon triggering the initiation of glomerular lesions. This study aimed to assess the rate of glomerular cell death and its relationship with renal functional, structural and molecular changes in rats with experimental diabetes. Methods Male Sprague-Dawley rats with streptozotocin-induced diabetes and coeval non-diabetic control animals were killed at 7 days and at 2, 4 and 6 months for the assessment of apoptosis, renal function, renal structure and the expression of podocyte markers and apoptosis- and cell cycle-related proteins. Results Glomerular cell apoptosis was significantly increased in diabetic vs non-diabetic rats at 4 months and to an even greater extent at 6 months, with podocytes accounting for 70% of apoptosing cells. The increase in apoptosis was preceded by increases in proteinuria, albuminuria and mean glomerular and mesangial areas, and by reductions in glomerular cell density and content of synaptopodin and Wilms' tumour protein-1. It coincided with the development of mesangial expansion and glomerular sclerosis, and with the upregulation/activation both of tumour protein p53, which increased progressively throughout the study, and of p21 (also known as cyclin-dependent kinase inhibitor 1A, CIP1 and WAF1), which peaked at 4 months and decreased thereafter. Conclusions/interpretation Glomerular cell (podocyte) apoptosis is not an early feature in the course of experimental diabetic glomerulopathy, since it is preceded by glomerular hypertrophy, which may decrease glomerular cell density to the point of inducing compensatory podocyte hypertrophy. This is associated with reduced podocyte protein expression (podocytopathy) and proteinuria, and ultimately results in apoptotic cell loss (podocytopenia), driving progression to mesangial expansion and glomerular sclerosis.