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Linking Metabolism and Immunology: Diabetic Nephropathy Is an Inflammatory Disease

Katherine R. Tuttle
JASN June 2005, 16 (6) 1537-1538; DOI: https://doi.org/10.1681/ASN.2005040393
Katherine R. Tuttle
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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 renin-angiotensin 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–β (PKC-β), 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-β, 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 complications (16). The data reported by Kelly and colleagues provide further scientific rationale and biologic plausibility for how this drug may ameliorate kidney disease even when hyperglycemia and hypertension are not well controlled, a situation all too common in the clinical realm (11). Second, on the scientific side, mechanisms of PKC-β activation and its actions provide insight into how a classic metabolic disease, diabetes, is linked to an immunological signature, inflammation. PKC is composed of at least 12 isoforms which signal a number of cellular responses, including oxidative stress, activation and/or expression of inflammatory mediators, cellular proliferation, and tissue fibrosis (16). Various PKC isoforms, particularly PKC-β, are activated in diabetes. Hyperglycemia, acting through generation of cellular diacylglycerol, is a predominant PKC activator, but advanced glycation end products (AGE) and other metabolic products may also participate in activation (16).

Intracellular adhesion molecule (ICAM)-1 is expressed on the surface of a number of cell types in response to PKC activation (17–19). ICAM-1 promotes inflammation by enhancing leukocyte infiltration and adherence. In a complementary paper, Chow and colleagues illustrate yet another dimension of the link between diabetes and inflammation by examining the role of ICAM-1 in glomerular and tubulointerstitial disease in db/db mice (12). These mice spontaneously develop hallmarks of type 2 diabetes, including hyperglycemia, hyperinsulinemia, and obesity. Their kidney disease is manifest by albuminuria, decreased GFR, glomerular hypertrophy and cellularity, and tubular atrophy and fibrosis. The conventional db/db mice were compared with a strain deficient in ICAM-1 using a gene knockout strategy, as well as to lean heterozygote controls. In db/db mice, ICAM-1 expression was increased in glomeruli and tubules, along with a marked increase in macrophage infiltration. ICAM-1 deficiency decreased most manifestations of kidney disease and macrophage accumulation in db/db mice. Further in vitro studies showed that rat macrophages cultured with either a high level of glucose or an AGE-modified protein produced increased amounts of active TGF-β. Conditioned media from AGE-stimulated macrophages caused cultured rat proximal tubular epithelial cells to produce ICAM-1. These data suggest that macrophage stimulation by hyperglycemia or AGE may augment pro-fibrotic responses of resident kidney cells and enhance their expression of ICAM-1. Thus, the paper by Chow and colleagues strongly implicates ICAM-1–induced inflammation in the pathogenesis of glomerular and tubulointerstitial disease in a model of type 2 diabetes and provides evidence that cellular responses are directly induced by metabolic disturbances.

In conclusion, diabetic nephropathy can be viewed as an inflammatory disease triggered by disordered metabolism. PKC-β, a cellular signaling mediator activated by hyperglycemia and associated metabolic disturbances, has been targeted for a novel therapeutic class that has moved into clinical trials for diabetic nephropathy. The rationale for targeting an inflammatory mechanism, ICAM-1, is emerging and may lead to yet another therapeutic class. If findings such as these can be fully translated into clinical treatments, hopes for better strategies to reduce the burden of diabetic nephropathy may be realized.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • © 2005 American Society of Nephrology

References

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    United States Renal Data System: Annual Data Report: Incidence and prevalence, 2001. Am J Kidney Dis 38 : S37 –S52, 2001
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  6. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: A randomized prospective 6-year study. Diabetes Res Clin Pract 28 : 103 –117, 1995
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  7. United Kingdom Prospective Diabetes Study (UKPDS) Group: Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352 : 837 –853, 1998
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  8. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329 : 1456 –1462, 1993
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  9. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345 : 861 –869, 2001
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    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345 : 851 –860, 2001
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    Kelly DJ, Chanty A, Gow RM, Zhang Y, Gilbert RE: Protein kinase C beta inhibition attenuates osteopontin expression, macrophage recruitment, and tubulointerstitial injury in advanced experimental nephropathy. J Am Soc Nephrol 16 : 1654 –1660, 2005
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    Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins RC, Tesch GH: Intracellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice. J Am Soc Nephrol 16 : 1711 –1722, 2005
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    Kelly DJ, Wilkinson-Berka JL, Allen TJ, Cooper ME, Skinner SL: A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (TGR). Kidney Int 54 : 343 –352, 1998
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    Nikolic-Paterson DJ, Atkins RC: The role of macrophages in glomerulonephritis. Nephrol Dial Transplant 16[Suppl 5] : 3 –7, 2001
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    Gilbert RE, Cooper ME: The tubulointerstitium in progressive diabetic kidney disease: More than an aftermath of glomerular injury? Kidney Int 56 : 1627 –1637, 1999
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    Tuttle KR, Anderson PW: A novel potential therapy for diabetic nephropathy and vascular complications: Protein kinase C beta inhibition. Am J Kidney Dis 42 : 456 –465, 2003
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    Park CW, Kim JH, Lee JW, Kin YS, Ahn HJ, Shin YS, Kim SY, Choi EJ, Chang YS, Bang BK: High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-chiB-dependent. Diabetologia 43 : 1544 –1553, 2000
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Journal of the American Society of Nephrology: 16 (6)
Journal of the American Society of Nephrology
Vol. 16, Issue 6
1 Jun 2005
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Linking Metabolism and Immunology: Diabetic Nephropathy Is an Inflammatory Disease
Katherine R. Tuttle
JASN Jun 2005, 16 (6) 1537-1538; DOI: 10.1681/ASN.2005040393

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Linking Metabolism and Immunology: Diabetic Nephropathy Is an Inflammatory Disease
Katherine R. Tuttle
JASN Jun 2005, 16 (6) 1537-1538; DOI: 10.1681/ASN.2005040393
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