Nephropathy in a hypercholesterolemic mouse model with streptozotocin-induced diabetes.
OBJECTIVE
The contribution of preexisting hypercholesterolemia to diabetic nephropathy remains unclear. We assessed the impact of hypercholesterolemia on diabetic nephropathy using a double knockout (DKO) mouse, null for the low-density lipoprotein receptor (LDLRNDASH;/NDASH;) and the apoB mRNA editing catalytic polypeptide 1 (APOBEC1NDASH;/NDASH;).


METHODS
Wild-type (WT) and DKO mice received sham or streptozotocin injections at age 7 weeks, yielding control (WT-C, DKO-C) and diabetic (WT-D, DKO-D) groups. At sacrifice (age 40 weeks), albuminuria was determined by ELISA, and kidney sections were examined by light and electron microscopy.


RESULTS
Albuminuria increased in diabetic mice (WT-D: 82.4 +/- 37.2 microg/18 h; DKO-D: 58.0 +/- 45.7 microg/18 h) versusnondiabetic controls (WT-C: 10.2 +/- 7.2 microg/18 h; DKO-C: 8.6 +/- 5.3 microg/18 h) (p LT; 0.0001), but was unaffected by hypercholesterolemia. Light microscopy of kidney sections demonstrated increased collagen levels in glomeruli in WT-D mice, but not in DKO-D mice or either control group. Electron microscopy showed a thickened glomerular basement membrane in WT-D mice only. The proximal tubular basement membrane thickness was increased in both diabetic groups versusnondiabetic controls (p LT; 0.01); in WT-D mice this was attributable to collagen accumulation, but in DKO-D mice it was mainly caused by lipid vacuoles.


CONCLUSIONS
In this animal model, preexisting hypercholesterolemia did not exacerbate either glomerular lesions of diabetes (collagen accumulation, basement membrane thickening) or albuminuria, but appeared to mitigate these effects. Furthermore, the combination of hypercholesterolemia and diabetes resulted in a significant lipid accumulation in the tubular basement membrane.
Hammad
Samar M
SM
Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, Charleston 29425, USA. hammadsm@musc.edu
Hazen-Martin
Debra J
DJ
Sohn
Mimi
M
Eldridge
Leslie
L
Powell-Braxton
Lyn
L
Won
Wesley
W
Lyons
Timothy J
TJ
D000071479:APOBEC-1 Deaminase; D000419:Albuminuria; D000818:Animals; D001161:Arteriosclerosis / Q000150:complications; D001485:Basement Membrane / Q000737:chemistry / Q000473:pathology; D003094:Collagen / Q000032:analysis; D003564:Cytidine Deaminase / Q000172:deficiency; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications*; D007668:Kidney / Q000033:anatomy & histology / Q000737:chemistry / Q000473:pathology; D007684:Kidney Tubules / Q000737:chemistry / Q000473:pathology; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D011973:Receptors, LDL / Q000172:deficiency; D013311:Streptozocin
D008055:Lipids; D011973:Receptors, LDL; D013311:Streptozocin; D003094:Collagen; D000071479:APOBEC-1 Deaminase; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase