The Genetics of Hypertension Modifies the Renal Cell Replication Response Induced by Experimental Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 5; pp. 1529 - 1534
• Main Authors: SILVEIRA, Lilia A, BACCHI, Carlos E, PINTO, Glauce A, LOPES DE FARIA, José B
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2002
• Subjects: Animals; Antigens; Associated diseases and complications; Biological and medical sciences; Cell Cycle Proteins - metabolism; Cell Division - genetics; Cell growth; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-dependent kinases; Cyclins - metabolism; Development and progression; Diabetes; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - pathology; Diabetes research; Diabetes. Impaired glucose tolerance; Diabetic nephropathies; Diabetic Nephropathies - genetics; Diabetic Nephropathies - pathology; Diabetic nephropathy; Disease susceptibility; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Genetic aspects; Genetic Predisposition to Disease; Hypertension; Hypertension, Renal - genetics; Hypertension, Renal - pathology; In Situ Nick-End Labeling; Insulin; Kidney Glomerulus - pathology; Kinases; Medical sciences; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tumor Suppressor Proteins - metabolism; Brazil; Endocrinopathy; Hypertension; Animal model; Rat; Diabetes mellitus; Rodentia; Cardiovascular disease; Kidney; Vertebrata; Mammalia; Urinary system; Animal; Complication; Genetics; Replication
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.51.5.1529

The Genetics of Hypertension Modifies the Renal Cell Replication Response Induced by Experimental Diabetes Lilia A. Silveira 1 , Carlos E. Bacchi 2 , Glauce A. Pinto 3 and José B. Lopes de Faria 1 1 Renal Pathophysiology Laboratory, Nephrology Unit, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil 2 Department of Pathology, Faculty of Medical Sciences, State University of São Paulo (UNESP), Botucatu, São Paulo, Brazil 3 Experimental Pathology Laboratory, University Hospital, UNICAMP, Campinas, São Paulo, Brazil Abstract To investigate whether the genetics of hypertension modifies renal cell responses in experimental diabetes, we studied the renal cell replication and its regulation by two cyclin-dependent kinase (Cdk) inhibitors, p27 Kip1 and p21 Cip1 , in prehypertensive spontaneously hypertensive rats (SHR) and their genetically normotensive counterparts, Wistar Kyoto (WKY) rats, with and without streptozotocin-induced diabetes. In diabetic SHR, the number of proliferating glomerular (0.6 ± 0.3 positive cells/50 glomeruli) and tubulointerstitial (2.8 ± 0.6 positive tubulointerstitial cells/50 grid fields) cells assessed by the bromodeoxyuridine technique was significantly ( P = 0.0002) lower than in control SHR (13.2 ± 1.7 and 48.6 ± 9.7, respectively) and control (14.0 ± 1.8 and 63.9 ± 10.6) and diabetic (14.3 ± 3.5 and 66.4 ± 11.5) WKY rats. Proliferating cell nuclear antigen, another marker of cell proliferation, was significantly reduced in replicating glomerular ( P = 0.0002) and tubulointerstitial ( P < 0.0001) cells in diabetic SHR. In freshly isolated glomeruli, the level of p27 Kip1 detected by Western blotting was significantly higher in diabetic SHR than in nondiabetic SHR (1.52 ± 0.14 vs. 1.00 ± 0.10% of control, P = 0.014). The expression of p21 Cip1 in isolated glomeruli did not differ among the groups of rats. In conclusion, the response of renal cell replication to diabetes differs markedly between prehypertensive SHR and their WKY control rats. The decreased glomerular cell proliferation in prehypertensive diabetic SHR is at least partly mediated by a higher expression of the Cdk inhibitor p27 Kip1 . Footnotes Address correspondence and reprint requests to Dr. José B. Lopes de Faria, Renal Pathophysiology Laboratory, Nephrology Unit, Faculty of Medical Sciences, UNICAMP, Campinas, São Paulo, Brazil. E-mail: jblfaria{at}fcm.unicamp.br . Received for publication 9 February 2001 and accepted in revised form 14 January 2002. ABC, avidin-biotin complex; BrdU, 5-bromo-2′-deoxyuridine; Cdk, cyclin-dependent kinase; DAB, diaminobenzidine tetrahydrochloride; PCNA, proliferating cell nuclear antigen; STZ, streptozotocin; TdT, terminal deoxynucleotidyl transferase; TGF, transforming growth factor; TUNEL, TdT-mediated dUTP-biotin nick-end labeling. DIABETES