TY - JOUR
T1 - Inhibition of diabetic nephropathy by a GH antagonist
T2 - A molecular analysis
AU - Esposito, Ciro
AU - Liu, Zhi Hong
AU - Striker, Gary E.
AU - Phillips, Carrie
AU - Chen, Nian Yi
AU - Chen, Wen Y.
AU - Kopchick, John J.
AU - Striker, Liliane J.
N1 - Funding Information:
Acknowledgments CE and ZHL have contributed equally to the work and are both to be considered first authors. Ciro Esposito was supported by the Mentor-Based Postdoctoral Fellowship Program of the American Diabetes Association to US. This work was supported, in part, by the state of Ohio's Eminent Scholar Program, which includes a grant from Milton and Lawrence Go!! (to JJK), by NIH grant 42137-O1AZ, and by USDA grant 92-37206-7847.
PY - 1996
Y1 - 1996
N2 - Streptozotocin-treated C57B1/SJL mice developed glomerular hypertrophy and light microscopic lesions mimicking human diabetic glomerulosclerosis. In contrast, there were no glomerular hypertrophy and lesions in diabetic mice transgenic (TG) for a mutated growth hormone (bGH-G119K) that competes with native endogenous GH and results in dwarfism. We examined the molecular events underlying these findings. The non-transgenic (non-TG) diabetic mouse glomeruli had an increase in mRNA coding for αIIV collagen, laminin B1, TGF-β1, 72 kDa collagenase, and TIMP-3. In contrast, glomerular type IV collagen and laminin B1 mRNA levels were normal in diabetic TG dwarf mice. However, the 72 kDa gelatinase. TIMP-3, and TGF-β1 mRNAs were elevated in the diabetic dwarfs. Type IV collagen and laminin accumulated in the glomeruli of diabetic non-TG, but not of diabetic dwarf mice, by immunofluorescence microscopy, confirming the mRNA data. GH binding protein mRNA levels were comparable in glomeruli from dwarf and non-TG mice, both diabetic and non-diabetic. We did not detect GH receptor mRNA in glomeruli. These data suggest that diabetic glomerulosclerosis is associated with an increase in type IV collagen and laminin synthesis, and that these changes do not occur in mice transgenic for bGH119K, a functional antagonist of GH. The increase of 72 kDa gelatinase, TIMP-3, and TGF-β1 mRNAs, independent of GH, suggested that these changes induced by hyperglycemia were not sufficient for the induction of glomerulosclerosis.
AB - Streptozotocin-treated C57B1/SJL mice developed glomerular hypertrophy and light microscopic lesions mimicking human diabetic glomerulosclerosis. In contrast, there were no glomerular hypertrophy and lesions in diabetic mice transgenic (TG) for a mutated growth hormone (bGH-G119K) that competes with native endogenous GH and results in dwarfism. We examined the molecular events underlying these findings. The non-transgenic (non-TG) diabetic mouse glomeruli had an increase in mRNA coding for αIIV collagen, laminin B1, TGF-β1, 72 kDa collagenase, and TIMP-3. In contrast, glomerular type IV collagen and laminin B1 mRNA levels were normal in diabetic TG dwarf mice. However, the 72 kDa gelatinase. TIMP-3, and TGF-β1 mRNAs were elevated in the diabetic dwarfs. Type IV collagen and laminin accumulated in the glomeruli of diabetic non-TG, but not of diabetic dwarf mice, by immunofluorescence microscopy, confirming the mRNA data. GH binding protein mRNA levels were comparable in glomeruli from dwarf and non-TG mice, both diabetic and non-diabetic. We did not detect GH receptor mRNA in glomeruli. These data suggest that diabetic glomerulosclerosis is associated with an increase in type IV collagen and laminin synthesis, and that these changes do not occur in mice transgenic for bGH119K, a functional antagonist of GH. The increase of 72 kDa gelatinase, TIMP-3, and TGF-β1 mRNAs, independent of GH, suggested that these changes induced by hyperglycemia were not sufficient for the induction of glomerulosclerosis.
UR - https://www.scopus.com/pages/publications/0029832429
U2 - 10.1038/ki.1996.342
DO - 10.1038/ki.1996.342
M3 - Article
C2 - 8840279
AN - SCOPUS:0029832429
SN - 0085-2538
VL - 50
SP - 506
EP - 514
JO - Kidney International
JF - Kidney International
IS - 2
ER -