Podocytes are specialized differentiated cells, and loss of podocyte cells or podocyte foot process effacement are prominent features of diabetic nephropathy (Clement et al., 2011). GR and circulatory angiopoietin-like 4 proteins regulate podocyte-endothelium health and GR loss in podocytes leading to proteinuria and glomerulosclerosis in diabetes (Clement et al., 2014; Srivastava et al., 2021b). Epigenetic alterations, DNA methylation, and inability in DNA damage repair in diabetic podocytes are directly associated with diabetic nephropathy (DN) phenotypes. Vermon et al. study demonstrated the critical role of podocyte VEGF-A in the diffused glomerulosclerosis in diabetic and eNOS mutant mice. Deletion of VEGF-A in podocytes induced the abnormal S-nitrosylation of specific proteins, including β-integrin and laminin, which are involved in the development of diffused glomerulosclerosis, suggesting the essential role of VEGF-A and nitric oxide in the glomerular homeostasis and pathogenic roles of S-nitrosylated β-integrin and laminin in the glomerular disease, implicating the significant advances in podocyte cell biology (Vermon et al.). In addition, aberrant levels of ferroptosis, pyroptosis, necroptosis, and apoptosis are important phenomena in DN, linked with the activation of fibrogenic pathways in tubules and podocytes. Understanding gasdermin D mediated pyroptosis provides valuable insights into DN research. Another part of the study describes the role of mineralocorticoid receptor (MR) in diabetic kidney disease (DKD). MR antagonism reversed DKD phenotypes by suppressing fibrosis, oxidative stress, and inflammation (Kawanami et al.). Therefore, an enhanced understanding of MR biology in diverse cell types is important for DKD management.

The use of SGLT2 inhibitors as safe therapeutics in diabetic kidney disease has recently been widely studied in preclinical settings and randomized clinical trials. The function of SGLT2 is to reabsorb urine glucose filtered from the glomerulus. The EMPA-REG trial has demonstrated that empagliflozin suppressed diabetic nephropathy phenotypes, and this study represents a crucial development in the clinical practice of diabetes management (Mayer et al., 2019). Data in mouse models suggest that SGLT2 inhibitors suppress the pathogenic abnormal glycolysis levels and restore the fatty acid oxidation levels in the tubules, improving tubular health (Li et al., 2020b).

One of the studies included in this issue imparts significant information on dapagliflozin in tubule protection. However, high salt diet intake compromised the tubular protection of dapagliflozin in diabetic patients and mouse models of DKD. These data demonstrate that high-salt diet intake impairs the tubule fatty acid metabolism, a key contributor of renal fibrosis in diabetes (Zou et al.). In addition, SGLT2 inhibitors are effective against autophagic defects in metabolic diseases. Autophagic improvement by SGLT2 inhibitors would be of great significance and usher the need for future randomized clinical trials to evaluate the SGLT2 inhibitors in autophagy defects related metabolic diseases. Zhang et al. tested the recombinant anti-IL6R fusion proteins in the mouse models of diabetic nephropathy and found that reducing DN phenotypes by mitigating the JAK2/STAT3 signal transduction pathway is effective, suggesting the pathobiology of IL-6R/JAK2/STAT3 pathway in DN (Zhang et al.). In recent years, ROCK inhibitors have been shown to effectively improve renal outcomes of diabetic patients suggesting the possibility of a potential lead in DKD.

This Research Topic discussed the crucial pathways that will enlighten possible future therapeutics against fibrogenesis and vascular dysfunction in diabetes. The information gained from this Research Topic will be useful for clinicians and basic science researchers to guide novel therapeutic approaches and future research directions.