The genetics of hypertension modifies the renal cell replication response induced by experimental diabetes.

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).

Early blood pressure normalization independent of the class of antihypertensive agent prevents augmented renal fibronectin and albuminuria in experimental diabetic nephropathy.

BACKGROUND/AIMS: This study tested the hypothesis that prevention of the development of hypertension, and not the class of antihypertensive agent, inhibits the increase in renal fibronectin and albuminuria in experimental diabetes. METHODS: Four-week-old spontaneously hypertensive rats (SHR), with diabetes induced by streptozotocin, were randomized for no treatment, or treatment with captopril, amlodipine, an association of captopril and amlodipine (Cap+A) or an association of captopril and verapamil (Cap+V) for 12 weeks. RESULTS: Systolic blood pressure increased similarly in control (187 +/- 5 mm Hg, mean +/- SE) and diabetic (186 +/- 4) SHR and was kept within the normal range by amlodipine (131 +/- 3), captopril (127 +/- 3), Cap+A (134 +/- 4) and Cap+V (134 +/- 9, p < 0.0001). In diabetic rats, albuminuria was higher than in control SHR [geometric mean (variance), 1,213 (953-1,708) vs. 512 (213-850), p < 0.0001] and was reduced to a similar extent by amlodipine [573 (353-744), p < 0.0001], captopril [562 (238-771), p < 0.0001], Cap+A [679 (442-971), p < 0.0001] and Cap+V [748 (581-848) microg/24 h, p = 0.0002]. Renal fibronectin increased in diabetic rats (24.0 +/- 3.3 densitometric units, mean +/- SE) compared to control rats (9.6 +/- 1.8, p = 0.0005) and was normalized by amlodipine (9.9 +/- 1.0, p = 0.0001), captopril (11.2 +/- 0.4, p = 0.0016), Cap+A (9.9 +/- 2.0, p = 0.0004) and Cap+V (14.7 +/- 4.9, p = 0.0159). CONCLUSION: In this model, tight blood pressure control rather than the class of antihypertensive agent was the main determinant factor in attenuating of nephropathy.