The Genetics of Hypertension Modifies the Renal Cell Replication Response Induced by Experimental Diabetes
- 1Renal Pathophysiology Laboratory, Nephrology Unit, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- 2Department of Pathology, Faculty of Medical Sciences, State University of São Paulo (UNESP), Botucatu, São Paulo, Brazil
- 3Experimental 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, p27Kip1 and p21Cip1, 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 p27Kip1 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 p21Cip1 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 p27Kip1.
Footnotes
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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
