The role of classical protein tyrosine phosphatases in diabetic kidney disease and therapeutic implications

Approximately one-third of people with diabetes have diabetic kidney disease (DKD), and DKD remains a leading cause of kidney failure in the United States. DKD is characterized by injury to the glomerular filtration barrier and renal tubulointerstitium, arising from complex and convergent metabolic, hemodynamic, and inflammatory insults. Tyrosine phosphorylation, a reversible post-translational modification, is a central regulatory mechanism in these pathways and is dynamically controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Aberrant tyrosine phosphorylation is a hallmark of DKD and implicates PTPs as key modulators of podocyte, endothelial, tubular, and immune cell dysfunction. Over 100 genes code for PTPs in humans, with 38 'classical' PTPs that specifically target tyrosine motifs, including receptor-type and non-receptor-type subtypes. Several classical PTPs are implicated in DKD pathogenesis, while others are increasingly associated with signaling cascades that drive renal metabolism, inflammation, fibrosis, and cell death. There is growing interest in PTPs as their contributions to the disease emerge, though the role(s) of some remain uncharacterized in DKD. Moreover, recent breakthroughs in pharmaceuticals targeting PTPs for metabolic diseases and cancer have ignited interest in repurposing or tailoring PTP‑directed therapeutics for DKD. This review summarizes current knowledge and recent advances of classical PTPs in DKD, including their roles in insulin signaling, cellular architecture, and glomerular and tubular cell injury. It further discusses existing DKD treatments and highlights emerging strategies to pharmacologically modulate PTP activity, such as active‑site inhibitors, allosteric agents, and antibody‑targeting approaches. By integrating mechanistic insights with drug discovery efforts, this review outlines how targeting specific PTPs could complement current standard‑of‑care therapies and open new avenues for precision treatment of DKD.