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Podocyte Depletion Causes Glomerulosclerosis: Diphtheria Toxin–Induced Podocyte Depletion in Rats Expressing Human Diphtheria Toxin Receptor Transgene

Bryan L. Wharram^*, Meera Goyal^*, Jocelyn E. Wiggins, Silja K. Sanden^*, Sabiha Hussain^*, Wanda E. Filipiak, Thomas L. Saunders^,, Robert C. Dysko^||, Kenji Kohno^¶, Lawrence B. Holzman^* and Roger C. Wiggins^*

Divisions of ^* Nephrology, Geriatric Medicine, and Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Transgenic Animal Model Core, ^|| Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, Michigan; and ^¶ Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Nara, Japan

Address correspondence to: Dr. Roger C. Wiggins, University of Michigan Health System, Division of Nephrology, Department of Internal Medicine, 1570 MSRBII, Box 0676, Ann Arbor, MI 48109-0676. Phone: 734-936-4813; Fax: 734-763-0982; E-mail: rwiggins{at}umich.edu

Received for publication January 15, 2005. Accepted for publication July 7, 2005.

Glomerular injury and proteinuria in diabetes (types 1 and 2) and IgA nephropathy is related to the degree of podocyte depletion in humans. For determining the causal relationship between podocyte depletion and glomerulosclerosis, a transgenic rat strain in which the human diphtheria toxin receptor is specifically expressed in podocytes was developed. The rodent homologue does not act as a diphtheria toxin (DT) receptor, thereby making rodents resistant to DT. Injection of DT into transgenic rats but not wild-type rats resulted in dose-dependent podocyte depletion from glomeruli. Three stages of glomerular injury caused by podocyte depletion were identified: Stage 1, 0 to 20% depletion showed mesangial expansion, transient proteinuria and normal renal function; stage 2, 21 to 40% depletion showed mesangial expansion, capsular adhesions (synechiae), focal segmental glomerulosclerosis, mild persistent proteinuria, and normal renal function; and stage 3, >40% podocyte depletion showed segmental to global glomerulosclerosis with sustained high-grade proteinuria and reduced renal function. These pathophysiologic consequences of podocyte depletion parallel similar degrees of podocyte depletion, glomerulosclerosis, and proteinuria seen in diabetic glomerulosclerosis. This model system provides strong support for the concept that podocyte depletion could be a major mechanism driving glomerulosclerosis and progressive loss of renal function in human glomerular diseases.

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