Pathology identifies glomerular treatment targets in diabetic nephropathy

Abstract

The development of the glomerular injury in diabetic nephropathy involves interactions between podocytes, endothelium, and the mesangium. Loss of podocytes is an early and critical step in the development of diabetic nephropathy, and analysis of structural lesions within the mesangium such as mesangiolysis implicate the loss of podocytes as a key mediating event. The BTBR ob/ob mouse has proved a useful tool to demonstrate that restoration of podocyte density, once thought to be an absolute barrier to glomerular repair, can be achieved with replacement of the hormone leptin that is constitutively absent in these mice. Restoration of podocyte density is associated with reversal of the structural lesions of morphologically advanced diabetic glomerular injury in this model. This finding, in conjunction with the demonstration in human diabetic patients with morphologically advanced diabetic nephropathy and with long-standing functioning pancreatic transplants of ten years duration that their diabetic nephropathy can be reversed, suggests that restoration of podocyte number and density is an appropriate target for the development of new therapeutics for diabetic nephropathy.

Keywords: Diabetic nephropathies; Histology; Pathology; Podocytes.

Figure 1. BTBR ob/ob mice develop marked mesangial matrix expansion and other glomerular changes of morphologically advanced diabetic nephropathy by 18 weeks of age (B) compared to wild type controls as exhibited in A

These changes are progressive, and can be reversed with six weeks of leptin administration beginning at 18 weeks of age when diabetic nephropathy has already well-established. C and D compare untreated mice and leptin treated mice at 24 weeks of age.

Figure 2. Immunohistochemistry staining with the marker WT-1 identifies podocytes in human and mouse glomeruli

Podocytes are lost in the course of progressive diabetic nephropathy in the BTBR ob/ob mouse, as they are in humans. A shows a normal complement of podocytes in wild type mice, with progressive loss of podocytes at 18 and 24 weeks of age in B and C. Treatment with leptin for six weeks results in full restoration of podocyte density (D), and is directly associated with the restoration of normal structure of glomeruli with this treatment as demonstrated in Fig. 1.