Phosphatases Emerge as Promising Targets Against Diabetic Kidney Disease

Diabetic kidney disease has long stood as one of medicine’s most stubborn adversaries, a complication that strikes roughly a third of people living with diabetes and remains a leading cause of kidney failure worldwide. Despite decades of progress in controlling blood sugar and blood pressure, many patients continue their inexorable slide toward dialysis and transplantation. Now, a sweeping review published in the Journal of Biomedical Science argues that a family of enzymes long overlooked in nephrology—the classical protein tyrosine phosphatases—may hold the key to fundamentally new treatments, offering mechanistic insight into why kidneys fail under diabetic stress and, crucially, how drugs already in development for cancer and metabolic disease could be redirected toward the kidney.

The numbers behind the review are sobering. Between 1990 and 2021, the global burden of chronic kidney disease driven by type 2 diabetes nearly doubled, reflecting an increase of roughly 80 to 90 percent. In the United States, annual all-cause healthcare costs for an insured patient with diabetic kidney disease climb from about 30,000 dollars in early stages to approximately 119,000 dollars as the disease advances. These figures capture more than economic strain; they reflect a disease whose cellular and molecular underpinnings remain only partially mapped, and whose progression is rarely reversible once structural injury takes hold. The authors of the review, Grace LeBleu and Fawaz G. Haj, contend that aberrant tyrosine phosphorylation—a reversible chemical switch that controls how cells respond to insulin, growth factors, and inflammatory cues—is a hallmark of diabetic kidney injury, and that the enzymes which remove these phosphate marks deserve far greater therapeutic attention.

Tyrosine phosphorylation is governed by a tug of war between two enzyme families: protein tyrosine kinases, which add phosphate groups to proteins, and protein tyrosine phosphatases, which remove them. While kinases have long been celebrated drug targets, phosphatases were for years dismissed as undruggable, largely because their catalytic pockets are highly conserved and positively charged, making selective inhibition difficult. The human genome encodes more than 100 phosphatase genes, of which 38 are classical phosphatases that specifically target phosphotyrosine residues—21 of the receptor-type and 17 of the non-receptor-type. The review systematically catalogs the evidence linking each of these 38 enzymes to diabetic kidney disease, ranging from directly established contributors to those implicated only indirectly or not at all.

Among the most firmly established is PTP1B, encoded by the PTPN1 gene. Discovered in the late 1980s and early 1990s as a negative regulator of insulin signaling, PTP1B dephosphorylates the insulin receptor and dampens downstream cascades. In podocytes—the specialized cells whose foot processes form the kidney’s filtration barrier—PTP1B knockdown stabilizes the cytoskeleton and preserves insulin signaling under high-glucose conditions. Recent work identified the cytoskeletal protein alpha-actinin-4 as a PTP1B substrate in insulin-stimulated podocytes, linking the enzyme directly to podocyte motility. In mouse models, global PTP1B deletion markedly attenuates glomerular injury and reduces albuminuria without major changes in blood glucose or pressure, while podocyte-specific deletion or pharmacological inhibition preserves podocyte architecture and blunts glomerular basement membrane thickening. Notably, PTP1B expression has been reported to be elevated in glomerular biopsies from patients with diabetic kidney disease, lending human relevance to the animal findings.

SHP2, the product of PTPN11, has emerged as another central player. In podocytes exposed to high glucose, SHP2 expression rises alongside increased endoplasmic reticulum stress, activation of the inflammatory transcription factor NF-κB, and heightened cell motility; silencing the enzyme prevents these changes. In diabetic mice, elevated SHP2 phosphorylation appears in macrophages, glomeruli, and podocytes, and podocyte-specific genetic deletion or pharmacological inhibition preserves renal function, lowering albuminuria and blood urea nitrogen. Immunohistochemical analysis of renal biopsies from patients with diabetic kidney disease reveals elevated phosphorylated SHP2 at a key activating site, and small-molecule inhibitors such as SHP099 and PHPS1 have shown renoprotective effects in rodent models of both type 1 and type 2 diabetes. SHP1, encoded by PTPN6, tells a similar story: hyperglycemia raises its expression in podocytes, disrupting insulin signaling and promoting apoptosis, while podocyte-specific deletion of SHP1 reduces albuminuria and reverses features of disease progression, apparently by restoring SUMOylation of the slit diaphragm protein podocin.

The review also spotlights endothelial and podocyte receptor-type phosphatases with distinctive renal roles. VEPTP, encoded by PTPRB, is largely restricted to endothelial cells in the adult kidney, where it dephosphorylates the angiopoietin receptor TIE2. Hyperglycemia, osmotic stress, and hypoxia all increase VEPTP expression, and inducible genetic deletion in diabetic mice improves glomerular filtration rate, reduces matrix accumulation, and preserves podocyte integrity—although an antibody-based inhibition approach alone failed to improve albuminuria, hinting that endothelial protection must be paired with therapies addressing the filtration barrier itself. CD148, encoded by PTPRJ, dephosphorylates growth factor receptors including VEGFR2 and EGFR, and an agonistic anti-CD148 antibody that boosts the enzyme’s activity attenuated albuminuria and mesangial expansion in diabetic mice. GLEPP1, encoded by PTPRO, sits on the apical surface of podocytes, and its deletion produces structurally abnormal foot processes, hypertension, and reduced filtration capacity, while its expression is diminished in sclerosed glomeruli from patients with diabetic kidney disease.

Beyond these established players, the review traces a broader web of phosphatases implicated in diabetes and renal pathology. TCPTP dephosphorylates the insulin receptor non-redundantly with PTP1B; its overexpression via gene therapy ameliorated albuminuria and renal morphology in diabetic mice, and its levels are reduced in patients with early-stage diabetic kidney disease. PEZ, or PTPN14, modulates the Hippo pathway through YAP and drives inflammatory and fibrotic signaling via TRIP6, with elevated expression detected in diabetic glomeruli and patient kidneys. RPTPζ serves as a receptor for interleukin-34, recruiting macrophages to injured tubules, while RPTPγ functions as a carbon dioxide and bicarbonate sensor in proximal tubular cells and rises in the serum as diabetic kidney disease progresses. Immune-associated phosphatases such as CD45, PTPN22, and HePTP connect renal inflammation and fibrosis to leukocyte signaling, and a cluster of enzymes including LAR, RPTPε, RPTPσ, and PTP-MEG2 modulate insulin signaling in muscle, liver, and adipose tissue, with several genetic variants linked to type 2 diabetes risk.

What makes the moment ripe for phosphatase-directed therapy is a confluence of pharmacological progress. Current standard care—RAAS blockade with ACE inhibitors or angiotensin receptor blockers, SGLT2 inhibitors validated by the DAPA-CKD, EMPA-KIDNEY, and CREDENCE trials, GLP-1 receptor agonists demonstrated in the FLOW trial, and the nonsteroidal mineralocorticoid receptor antagonist finerenone—slows disease but rarely reverses injury. Combination regimens are increasingly viewed as the path forward, and phosphatase modulators could slot into this framework as complementary agents. SHP2 inhibitors have already advanced through phase I, II, and III oncology trials, while the allosteric inhibitor SHP099 reduced albuminuria and blood urea nitrogen in diabetic mouse models. PTP1B inhibitors including ertiprotafib and trodusquemine reached clinical trials for type 2 diabetes and obesity, and an antisense oligonucleotide, IONIS-PTP-1BRx, lowered HbA1c and body weight in overweight patients with type 2 diabetes. VEPTP inhibition with AKB-9778 progressed to phase II trials for diabetic retinopathy, where patients showed a modest reduction in urinary albumin-to-creatinine ratio.

Novel modalities are expanding the toolbox further. Allosteric inhibitors that bind sites outside the conserved catalytic pocket promise improved selectivity, bivalent ligands engage both active and adjacent sites, and targeted protein degradation via PROTAC technology—exemplified by the SHP2 degrader SHP2-D26—offers a route to eliminate rather than merely inhibit the enzyme. Artificial intelligence and machine learning workflows have already been applied to PTP1B and SHP2 inhibitor discovery, helping overcome the historical barrier of conserved catalytic pockets by identifying selective binding modes and optimized physicochemical properties. The authors emphasize that pharmacological modulation need not mean inhibition in every case: for CD148, whose activity appears protective, an activation strategy is the goal, illustrating the nuanced directionality of phosphatase drug development.

The review’s bottom line is a call to translational action. Diabetic kidney disease remains the leading cause of end-stage renal failure, and existing therapies, however effective at slowing decline, rarely restore lost function. Classical protein tyrosine phosphatases sit upstream of the insulin, inflammatory, oxidative stress, and cytoskeletal cascades that converge to destroy the kidney in diabetes, and several are now pharmacologically tractable. The challenge ahead lies in bridging preclinical promise to clinical reality—defining cell-type-specific roles, establishing context-dependent effects in human disease, and testing phosphatase-targeted agents in combination with established therapies. If that bridge can be built, enzymes once written off as undruggable may finally deliver the precision treatments that patients with diabetic kidney disease have been waiting for.

Subject of Research: The roles of classical protein tyrosine phosphatases in the pathogenesis and treatment of diabetic kidney disease

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

Article References: LeBleu, G., & Haj, F. G. (2026). The role of classical protein tyrosine phosphatases in diabetic kidney disease and therapeutic implications. Journal of Biomedical Science, 33(1), Article 89. https://doi.org/10.1186/s12929-026-01282-7

Image Credits: AI Generated

DOI: 10.1186/s12929-026-01282-7

Keywords: diabetic kidney disease, protein tyrosine phosphatases, PTP1B, SHP2, podocytes, insulin signaling, renal fibrosis, SGLT2 inhibitors, phosphatase inhibitors, drug discovery, chronic kidney disease, inflammation