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Amelioration of Diabetic Nephropathy in SPARC-Null Mice

Sekiko Taneda^*, Jeffrey W. Pippin, E. Helene Sage, Kelly L. Hudkins^*, Yasuo Takeuchi, William G. Couser and Charles E. Alpers^*

*Department of Pathology, Division of Nephrology, University of Washington, Seattle Washington; and Department of Vascular Biology, The Hope Heart Institute, Seattle, Washington.

Correspondence to Dr. Charles E. Alpers, University of Washington Medical Center, Department of Pathology, Box 356100, 1959 NE Pacific St., Seattle, WA 98195. Phone: 206-543-5616; Fax: 206-543-3644;

ABSTRACT. SPARC (Secreted Protein, Acidic and Rich in Cysteine) is a matricellular protein that inhibits mesangial cell proliferation and also affects production of extracellular matrix (ECM) by regulating transforming growth factor-1 (TGF-1) and type I collagen in mesangial cells. This study is an investigation of the role of SPARC in streptozotocin (STZ)–induced diabetic nephropathy (DN) of 6-mo duration in wild type (WT) and SPARC-null mice. SPARC expression was evaluated by immunohistochemistry (IHC) and by in situ hybridization (ISH). Deposition of type I and IV collagen and laminin was evaluated by IHC, and TGF- 1 mRNA was assessed by ISH. Renal function studies revealed no significant difference in BUN between diabetic SPARC-null mice and diabetic WT mice, whereas a significant increase in albumin excretion was detected in diabetic WT relative to diabetic SPARC-null mice. Diabetic WT animals exhibited increased levels of SPARC mRNA and protein in glomerular epithelial cells and in interstitial cells, in comparison with nondiabetic WT mice. Neither SPARC mRNA nor protein was detected in SPARC-null mice. Morphometry revealed a significant increase in the percentage of the glomerular tufts occupied by ECM in diabetic WT compared with nondiabetic WT mice, although there was no difference in the mean glomerular tuft area among groups. In contrast, diabetic SPARC-null mice did not show a significant difference in the percentage of the glomerular tufts occupied by ECM relative to nondiabetic null mice. Tubulointerstitial fibrosis was ameliorated in diabetic SPARC-null mice compared with diabetic WT animals. Further characterization of diabetic SPARC-null mice revealed diminished glomerular deposition of type IV collagen and laminin, and diminished interstitial deposition of type I and type IV collagen correlated with decreases in TGF- 1 mRNA compared with WT diabetic mice. These observations suggest that SPARC contributes to glomerulosclerosis and tubulointerstitial damage in response to hyperglycemia through increasing TGF- 1 expression in this model of chronic DN. E-mail: calp@u.washington.edu

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