Linking Metabolism and Immunology: Diabetic Nephropathy Is an Inflammatory Disease

Abstract

Diabetic nephropathy is one of the most important concerns in nephrology, as well as in medicine at large. Rapidly increasing rates of diabetes throughout the developed world represent an emerging epidemic with profound consequences. This epidemic is likely to drive previously unforeseen rates of vascular target organ complications. As survival from acute cardiovascular complications continues to improve, management of chronic complications such as kidney disease assume ever-larger roles. Diabetes is the leading cause of end-stage renal disease in the United States, accounting for approximately 45% of incident cases and 55% of prevalent cases in the present decade (1,2). End-stage renal disease in diabetes, particularly type 2, has been described as a medical catastrophe of worldwide dimensions (3). So what can be done to reduce the burden of diabetic nephropathy? Available therapies shown to prevent or slow progression should be broadly applied. These therapies include strict glycemic control and treatment of hypertension with inhibitors of the reninangiotensin system (4–10). However, in recent clinical trials in which care was presumably optimized, renoprotecion was far from complete. And, in reality, controlling hyperglycemia and hypertension in usual care settings is often more challenging than in clinical trials. Hence, even more effective therapies that interrupt mechanisms of kidney damage induced by hyperglycemia and/or hypertension are urgently needed. The bench-to-bedside paradigm of translational research is that two-way street where the clinic and the laboratory meet. For clinicians and patients, this is an opportunity to obtain more effective therapies. For scientists, discovery and technology can be applied to a meaningful clinical problem. Two elegant papers in this issue of the journal illustrate the hope of translational research (11,12). The paper by Kelly and colleagues utilized a model of diabetes and hypertension produced by administration of streptozotocin to a rat transgenic for the renin gene (11). Groups of diabetic and control rats were treated, or not, with an inhibitor of protein kinase C– (PKC-), ruboxistaurin. Although glomerular pathology has been well characterized in this model, the current paper emphasizes the importance of tubulointerstitial injury (11,13). Macrophage accumulation and injury at this site correlate closely with loss of kidney function in humans and animals with a range of kidney diseases, including diabetic nephropathy (14,15). This model of diabetes and hypertension demonstrated numerous macrophages in the interstitium of untreated rats, along with widespread and intense tubular staining for osteopontin, a protein known to recruit macrophages (11). Pro-fibrotic injury markers (interstitial collagen, tubular TGF-, and a marker of its activity, phosphorylated Smad2) were also increased. Despite persistent hyperglycemia and hypertension, albuminuria was reduced, and renal function was preserved in rats treated with ruboxistaurin. Moreover, tubulointerstitial macrophage accumulation, osteopontin expression, and pro-fibrotic injury markers were returned to control levels by this treatment. These observations have important translational implications. First, ruboxistaurin has already moved into clinical trials for diabetic nephropathy, as well as for other microvascular