Hyperglycemia alters renal cell responsiveness to pressure in a model of malignant hypertension.
OBJECTIVE
Poor glycemic control contributes to development of diabetic nephropathy. However, for a majority of clinical situations, the mechanisms responsible for high glucose-induced aggravation of renal tissue injury are not fully elucidated. We investigated responsiveness to pressure of various renal cell subsets subjected to hyperglycemic environment in an in-vitro model of malignant hypertension.


METHODS
Rat renal mesangium, epithelium and endothelium were exposed to high glucose-containing medium for 10 days and then subjected to high hydrostatic pressure for 1 h to simulate the incidence of malignant hypertension. In some cultures, renin-angiotensin system was experimentally suppressed prior to pressure application. Proliferation, apoptosis, intrarenal p53, H2O2 and angiotensin-II synthesis were subsequently assessed.


RESULTS
By contrast to cultures not exposed to high glucose, in all hyperglycemic cells p53 expression, angiotensin-II synthesis and apoptosis were increased, whereas proliferation depressed, irrespective of pressure enforcement. H2O2 release was enhanced by high pressure per se, and increased further following exposure to high glucose. In all diabetic cultures, inhibition of p53 by a specific inhibitor pifithrin concomitantly significantly decreased apoptosis.


CONCLUSIONS
Hyperglycemic environment alters responsiveness of renal cells to in-vitro simulation of malignant hypertension. The main consequence of either malignant hypertension or hyperglycemia is exaggerated apoptosis. However, the operating mechanisms differ: Malignant hypertension stimulates renal cell apoptosis via increased angiotensin-II, whereas hyperglycemia elicits apoptosis via augmented p53. By contrast to pressure-induced excessive proliferation of normoglycemic cells, hyperglycemia prohibits elevated proliferation in response to pressure. Angiotensin-II production is maximally augmented by hyperglycemic environment and is not stimulated further by pressure application.
Efrati
Shai
S
Research and Development Department, Assaf Harofeh Medical Center, Zerifin, Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Israel.
Berman
Sylvia
S
Tov
Yariv Siman
YS
Averbukh
Zhan
Z
Weissgarten
Joshua
J
D000804:Angiotensin II / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D006874:Hydrostatic Pressure; D006943:Hyperglycemia / Q000503:physiopathology*; D006974:Hypertension, Malignant / Q000503:physiopathology*; D007668:Kidney / Q000166:cytology; D050527:Mesangial Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D016159:Tumor Suppressor Protein p53; D000804:Angiotensin II; D006861:Hydrogen Peroxide