Cross Talk Between Macrophages and Podocytes in Diabetic Nephropathy: Potential Mechanisms and Novel Therapeutics

Abstract

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease and end-stage renal failure worldwide. Podocytes, essential components of the glomerular filtration barrier (GFB), are profoundly affected in the diabetic milieu, resulting in structural and functional alterations. Concurrently, macrophages, pivotal innate immune cells, infiltrate the diabetic kidney and exhibit diverse activation states influenced by the local environment, playing a crucial role in kidney physiology and pathology. This review synthesizes current insights into how the dynamic cross talk between these two cell types contributes to the progression of DN, exploring the molecular and cellular mechanisms underlying this interaction, with a particular focus on how macrophages influence podocyte survival through various forms of cell death, including apoptosis, pyroptosis, and autophagy. The review also discusses the potential of targeting macrophages to develop more effective treatments for DN.

Keywords: apoptosis; autophagy; diabetic nephropathy; macrophage; podocyte; pyroptosis.

Figure 1

Origins and phenotypes of macrophages in kidney. Renal macrophages can be originated from the differentiation of blood monocytes derived from hematopoietic stem cells in the bone marrow or exist as resident cells in tissues from early embryonic development. Tissue resident macrophages can be induced to form the M1 phenotype by LPS or IFN-γ stimulation and secrete inflammatory mediators, such as TNF-α and IL-1β, to exert a pro-inflammatory effect; moreover, they can also be transformed into the M2 phenotype activated by IL-4 and IL-13 and promote tissue repair via producing anti-inflammatory cytokines like IL-10 and TGF-β. This macrophage phenotype switch is a reversible and dynamic process in a diseased microenvironment in the DN. IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; TGF, transforming growth factor; TNF, tumor necrosis factor.

Figure 2

The effect of macrophages on death pathways of podocytes in DN. During DN progression, macrophages determine cell fate of podocytes through affecting multiple cell death processes, including apoptosis, pyroptosis, autophagy, necroptosis, and ferroptosis. AMPK, adenosine monophosphate-activated protein kinase; DUSP1, dual specificity protein phosphatase 1; MAPK, mitogen-activated protein kinase; NLRP3, the PYD domains-containing protein 3; RIPK1/3, receptor-interacting protein kinase 1 and 3; ROS, reactive oxygen species; TNF, tumor necrosis factor. ↑ indicates upregulation, ↓ indicates downregulation, and → indicates a promoting effect.

Figure 3

The regulatory role of macrophage-derived exosomes on podocytes DN. Macrophage-derived exosomes contain a variety of miRNAs, such as miR-21a-5p, miR-25-3p, and miR-93-5p, which enter into podocytes to target various genes and signaling pathways, influencing cell apoptosis. miRNA, microRNA; TLR4, Toll-like receptor 4; TNPO1/ATXN3, transportin-1/ataxin-3.