Macrophages directly mediate diabetic renal injury

Abstract

Monocyte/macrophage recruitment correlates strongly with the progression of renal impairment in diabetic nephropathy (DN), yet their direct role is not clear. We hypothesized that macrophages contribute to direct podocyte injury and/or an abnormal podocyte niche leading to DN. Experiments were conducted in CD11b-DTR mice treated with diphtheria toxin (DT) to deplete macrophages after streptozotocin-induced diabetes. Additional experiments were conducted in bone marrow chimeric (CD11b-DTR→ C57BL6/J) mice. Diabetes was associated with an increase in the M1-to-M2 ratio by 6 wk after the induction of diabetes. Macrophage depletion in diabetic CD11b-DTR mice significantly attenuated albuminuria, kidney macrophage recruitment, and glomerular histological changes and preserved kidney nephrin and podocin expression compared with diabetic CD11b-DTR mice treated with mutant DT. These data were confirmed in chimeric mice indicating a direct role of bone marrow-derived macrophages in DN. In vitro, podocytes grown in high-glucose media significantly increased macrophage migration compared with podocytes grown in normal glucose media. In addition, classically activated M1 macrophages, but not M2 macrophages, induced podocyte permeability. These findings provide evidence showing that macrophages directly contribute to kidney injury in DN, perhaps by altering podocyte integrity through the proinflammatory M1 subset of macrophages. Attenuating the deleterious effects of macrophages on podocytes could provide a new therapeutic approach to the treatment of DN.

Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy

“…Macrophage activation and recruitment is a characteristic feature of diabetic kidney disease, associated with both experimental and human DN (20)(21)(22)(23)27). We previously reported a fivefold increase (P = 0.001) in macrophage infiltration in the kidney cortex of diabetic WT mice after 16 weeks of STZ-induced diabetes, while no statistically significant change in macrophage infiltration was detected in the kidney of diabetic Hpse-KO mice (13).…”

“…In parallel, the view on DN as a consequence of solely metabolic/hemodynamic alterations has been transformed in recent years, with clear evidence indicating that the activation of innate immunity and chronic inflammation plays a significant role in the pathogenesis of both diabetes and its complications, including DN (18,19). Immunocytes (primarily macrophages) (19)(20)(21)(22)(23) and numerous inflammatory molecules such as nuclear factors (i.e., nuclear factor-kB [NF-kB]) and cytokines (i.e., tumor necrosis factor-a [TNF-a]) have been implicated in diverse pathogenic pathways related to DN (for review, see Navarro-González et al [18] and Lim and Tesch [19]). Macrophages are considered to be the major immune cells infiltrating the diabetic kidney and critically contributing to the development of renal damage (23,24).…”

“…Immunocytes (primarily macrophages) (19)(20)(21)(22)(23) and numerous inflammatory molecules such as nuclear factors (i.e., nuclear factor-kB [NF-kB]) and cytokines (i.e., tumor necrosis factor-a [TNF-a]) have been implicated in diverse pathogenic pathways related to DN (for review, see Navarro-González et al [18] and Lim and Tesch [19]). Macrophages are considered to be the major immune cells infiltrating the diabetic kidney and critically contributing to the development of renal damage (23,24). In the diabetic kidney, macrophages, activated by various elements of the diabetic milieu (DM) (e.g., high glucose [25], AGE [26,27], albumin [28], free fatty acids [29]), release reactive oxygen species and proinflammatory cytokines (e.g., TNF-a and interleukin-6), which cause injury to podocytes and tubular cells (18,24,30,31).…”

Relationship of Proinflammatory Cytokines With Microalbuminuria in Patients of Type 2 Diabetes Mellitus- Implications in the Pathogenesis of Diabetic Nephropathy

“…The phenomenon of glomerular as well renal interstitial infiltration by macrophages in patients of diabetic nephropathy is well known. 12 Therefore those glomeruli may be responsible for the increased levels of cytokine production where there has been cessation of macrophage infiltration. The evidence of chronic inflammation in patients with kidney failure or uraemia has been indicated by several studies.…”

Increased serum concentrations of inflammatory cytokines in type 2 diabetic patients with chronic kidney disease

“…Количество дан-ных клеток увеличивается по мере развития гломеруляр-ного и интерстициального фиброза [3][4][5][6]. Накапливается все больше данных о том, что воспалительные реакции c участием макрофагов играют важную роль в прогрессиро-вании ДН [6][7][8][9]. Воспалительные медиаторы -молекулы адгезии (ICAM-1, VCAM-1), интерлейкин-6 (IL-6) явля-ются биомаркерами прогрессирования нефропатии у больных СД-2 [10,11].…”