Enalapril treatment increases T cell number and promotes polarization towards M1-like macrophages locally in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is a serious complication of longstanding diabetes affecting up to 30% of all diabetes patients and is the main cause of end-stage kidney disease globally. Current standard treatment e.g. ACE-inhibitors like enalapril merely offers a delay in the progression leading to DN. Herein, we describe in two preclinical models evidence to local effects on the inflammatory signatures after intervention treatment with enalapril which provides enhanced understanding of the mechanism of ACE inhibitors. Enalapril transiently reduced albuminuria in both the db/db and the STZ-induced DN models with established disease, without modulating the HbA1c%. Albuminuria was strongly associated with loss of leukocytes, particularly B cells, but also of sub-populations of macrophages and CD4(+) T cells. The remaining kidney macrophages were polarized into a M2-like sub-population with reduced surface expression of the M1-like macrophage marker CD11c and enhanced expression of galectin-3. Enalapril treatment counteracted the reduction of leukocytes in the diabetic kidney towards levels noted in the non-diabetic kidney. Particularly, a subset of macrophages was increased and a clear expansion of CD4(+) and CD8(+) T cells was observed. However, enalapril failed to modulate the B cell compartment. Interestingly, enalapril treatment resulted in a re-polarization of the macrophages towards a M1-like phenotype characterized by elevated levels of CD11c with moderate down-regulation of the M2 marker galectin-3. The data demonstrate that ACE inhibition in pre-clinical models of DN shows a transient beneficial effect on albuminuria which is unexpectedly associated with restoration of T cells and M1-like macrophages in the kidney.

Galectin-3 in Renal Pathology: More Than Just an Innocent Bystander?

“…The surviving macrophages are an M2-like subpopulation with a decreased expression of the M1 marker and increased expression of galectin-3. Administration of enalapril to the db/db mice and the streptozotocin-induced diabetic nephropathy models with established disease resulted in a decreased albuminuria and a repopulation of M1-like phenotype macrophages and an expansion of CD4 + and CD8 + T cells [40] . …”

Macrophage polarization in kidney diseases

“…Consistently, increased infiltrating macrophages with M1 phenotype characterized by an elevated expression of inducible nitric oxide synthase and TNF-α are also evident in glomeruli and interstitium [47] , suggesting a M1 dominance in STZ DN. Interestingly, macrophages in the kidneys of STZ DN rat with increased albuminuria levels are characterized by an elevated expression of galectin-3 and TGF-β [48] , suggesting a M2 dominance. Although the species difference may contribute to the inconsistent findings, further investigation is necessary to determine the macrophage phenotypes in diabetic nephropathy.…”

“…Additionally, Toll-like receptor-2 knock-out promotes kidney macrophage M1 to M2 polarization shift, decreases albuminuria while restoring podocyte number and effacement [46] . However, enalapril treatment causing a re-polarization of the macrophages towards a M1-like phenotype appears to inhibit the progression of kidney damage in the same DN model [48] . These controversial findings about the role of macrophage phenotypes in DN may only be clarified with more careful studies.…”

Polarization of Macrophages in Metabolic Diseases

“…During the disease progression, the macrophages re-polarize locally in the kidney from an early CD11b + F4/80 low phenotype that potently contribute to apoptosis and tissue destruction to a CD11b + F4/80 high macrophage subtype that primarily enhance tissue remodelling and fibrosis present in late stage 3-4 DN [132]. We recently demonstrated in two pre-clinical models of advanced DN that macrophages indeed had re-polarized locally in the tissue towards a phenotype more resembling a mixed M2 to M1/M2-like phenotype with significantly reduced CD11c in combination with enhanced galectin-3 expression [69]. Macrophage galectin-3 strengthen TGFβR signalling by retaining cell surface expression of TGF-β receptors and thus the newly polarized diabetic kidney macrophage might provide novel insight to understand the tissue remodelling processes occurring in DN [133,134].…”

“…In CCR2 deficient mice a markedly reduced Ly6C high monocyte trafficking to the site of inflammation occurs suggesting that the CCR2b-CCL2 axis is essential for M1-like Ly6C high monocyte migration during metabolic conditions [68]. These Ly6C high monocytes accumulate in the diabetic kidney where they participate in progression of disease [69]. Table 1: M1 and M2 subgroups.…”