Table 3.

Main molecular mechanisms of DKD and their main findings summarized, as well as their association with published clinical trials [47].

Molecular Mechanisms of DKD	Main Findings	Association with Clinical Trials
Genetics and Epigenetics	DNA methylation, histone post-translational modifications, microRNA (miRNA), lcnRNA, and circRNA are exacerbated by hyperglycemia, promoting renal inflammation and fibrosis.	A cohort by van Zuydam et al associated the GABRR1 gene with microalbuminuria [13].
Innate Immunity	Macrophages and dendritic cells are activated by the interaction of TLRs and NLRs by hyperglycemia, leading to inflammation and renal injury. These cells require the presence of CSF-1.	A phase 2 randomized controlled clinical trial showed that baricitinib, a JAK1/2 inhibitor, reduces albuminuria in patients with type 2 DM. The JAK-STAT pathway is important in the initiation and regulation of innate and adaptive immunity [66].
Adaptive Immunity	Seen in lower proportion than innate immune cells; predominantly Th1 and Th17 cells. Increased expression of CD4+, CD8+, and CD20+ cells in DKD.	A phase 2 randomized controlled clinical trial showed that baricitinib, a JAK1/2 inhibitor, reduces albuminuria in patients with type 2 DM. The JAK-STAT pathway is important in the initiation and regulation of innate and adaptive immunity [66].
KKS	In hyperglycemia, the binding of bradykinin and kallidin metabolites to B1R induces an NK-Fβ-dependent pro-inflammatory response. B2R stimulation leads to a pro-inflammatory response via MAPK pathway.	A cross-sectional study by Härma et al measured plasma kallikrein activity in 295 individuals with type 1 DM, showing that lower levels of plasma kallikrein were associated with higher GFRs [67].
Cytokines and Chemokines	Cytokines including IL-1, IL-6, IL-18, (TNF-α), and IL-17 have a strong pro-inflammatory effect in the pathogenesis of DKD; chemokines include CCL2 (MCP-1), CCL5 (RANTES), and C-X3-C motif chemokine 1 (CX3CL1, fractalkine).	Patients with DKD from the CANTATA-SU trial showed that treatment with canagliflozin decreased circulating levels of IL-6, TNF receptor-1, matrix metalloproteinase-7, and fibronectin-1 [68].
Complement System	Activation of lectin and glycation of the complement regulatory protein CD 59 lead to activation of MAC and endothelial cell damage.
Aldosterone	Induces increased expression of TGF-β1 and type IV collagen in hyperglycemic conditions.	As shown in the FIDELIO-DKD trial and the FIGARO-DKD, finerenone, minelarocorticoid receptor blocker, has positive results in reducing kidney failure/progression and leads to a reduction in cardiovascular morbidity and mortality in patients with DKD [69,70].