Objective
Autoimmune diseases happen when the immune system mistakenly attacks the body’s own tissues. The kidney is a common and serious target of this process, leading to autoimmune nephropathy, which can develop into chronic kidney disease (CKD) and kidney failure. Despite its clinical significance, it remains unclear why the kidney is particularly vulnerable in Type 1 Diabetes (T1D) and how immune-mediated kidney damage begins and progresses. Current treatments mainly suppress the immune system, often causing severe side effects and providing limited long-term tissue repair. There is an urgent need to understand organ-specific mechanisms of kidney inflammation and to create more targeted therapies.
The kidney is lined with specialized epithelial cells that control fluid balance and waste removal. Among these, intercalated cells (ICs) have recently been identified as potential modulators of immune responses, yet their role in T1D-associated autoimmune kidney diseases remains largely unexplored. Our main goal is to understand how renal ICs influence immune activation, immune tolerance, and tissue repair during T1D-mediated nephropathy. We focus on two key signaling pathways—P2Y14 and IL-33—that we propose act as molecular "switches" determining whether kidney injury results in inflammation and scarring or in resolution and healing. We hypothesize that ICs function as immune sentinels in the kidney.
In T1D, damaged cells can release danger signals like UDP-glucose. Kidney ICs detect this signal via the P2Y14 receptor, which can trigger inflammation and tissue damage. During kidney injury, ICs release IL-33, a molecule that helps regulate immune responses, promote tolerance, and support tissue repair. Disrupting the balance between these inflammatory and protective signals hampers healing and can lead to chronic inflammation, fibrosis, and loss of kidney function.
Aim 1 of this project will examine how ICs communicate with immune cells during kidney injury through P2Y14. We hypothesize that P2Y14 in ICs promotes the production of mediators that attract immune cells, thereby driving kidney inflammation. By identifying the specific signals exchanged between ICs and immune cells, we will clarify how early inflammatory responses are initiated and maintained in T1D-associated autoimmune nephropathy.
Aim 2 will analyze how IL-33 restores immune balance and promotes repair after CKD. We hypothesize that IL-33 released by ICs signals to regulatory T cells (Tregs), a specialized subset of cells that suppresses harmful responses and promotes tissue healing. Through this IC–IL-33–Treg pathway, ICs help limit inflammation and support recovery. Failure of this pathway leads to unchecked immune activation, causing progressive kidney damage.
Aim 3 will study patients with T1D to find early warning signs of kidney disease. We believe that signals such as UDP-glucose and IL-33 can be detected in urine and blood before kidney irreversable problems appear, helping to predict who may develop CKD. Together, these studies will show that renal epithelial cells—often seen as passive targets of immune attack—actively influence immune responses in T1D. By explaining how ICs detect danger signals and regulate inflammatory versus healing immune pathways, this work will create a new framework for understanding autoimmune kidney disease.
Importantly, the mechanisms examined here are likely relevant beyond the kidney. Similar epithelial–immune interactions may contribute to tissue damage in other affected organs in T1D. By identifying key signaling pathways that regulate immune tolerance and tissue protection, this research can help develop more targeted therapies that prevent kidney damage while preserving normal immune function, ultimately improving outcomes for patients with T1D.
Background Rationale
Chronic kidney disease (CKD) is an increasing health issue affecting millions worldwide. About 25–50% of people with type 1 diabetes (T1D) develop kidney disease during their lives, showing a significant risk that remains even with good blood sugar control. Patients may experience a slow decline in kidney function, which can eventually lead to dialysis or a transplant. Current treatments mainly involve broad immunosuppression, which can raise the risk of infections and other serious side effects. More targeted, kidney-specific therapies are urgently needed for T1D.
Most research on T1D-related kidney disease has focused on the glomeruli (the kidney’s filtering units), but this does not fully explain why renal inflammation persists or worsens. The kidney also contains epithelial cells, long considered passive targets of injury. Among them, intercalated cells (ICs)—traditionally known for maintaining acid–base balance—are now recognized as active players that can sense tissue damage, communicate with immune cells, and help drive inflammation.
Kidney damage occurs not only because of blood sugar levels but also because the immune system—already attacking the pancreas—can affect other parts of the body, including the kidneys. During kidney injury, stressed renal cells release danger signals such as UDP-glucose. ICs detect UDP-glucose through the P2Y14 receptor, activating proinflammatory pathways and promoting the recruitment of immune cells to the kidney. Blocking P2Y14 helps protect the kidneys from damage in mouse models of Acute Kidney Injury. This suggests that targeting P2Y14 could be a promising new approach to preventing or treating kidney injury.
In response to kidney damage, ICs also produce IL-33, a molecule that helps regulate immune responses and supports tissue repair. IL-33 is known to influence regulatory T cells (Tregs), which generally help restrain harmful immune activity. In T1D, Tregs often fail to function properly, allowing inflammation to persist. Studies in preclinical models have shown that IL-33 can delay autoimmune responses in the pancreas by expanding Tregs, which help control excessive immune attacks.
Moreover, IL-33 neutralization has shown clinical benefits in inflammatory diseases like asthma. In patients with Type 2 Diabetic Kidney Disease, blocking IL-33 reduces renal inflammation but does not improve kidney function because most participants already have advanced CKD. Early intervention targeting IL-33–driven epithelial–immune signaling may prevent inflammatory kidney damage in T1D before it becomes irreversible. How ICs balance inflammatory and protective signals, and how disruptions in this balance contribute to chronic kidney damage, remains poorly understood. This knowledge gap limits our ability to develop treatments that address the root causes of kidney injury in T1D. By focusing on ICs and the signals they use to communicate with the immune system, this research aims to uncover mechanisms upstream of widespread immune activation. Importantly, early results show that blocking P2Y14 reduces kidney injury in animal models and that urinary UDP-glucose levels can serve as a marker of kidney damage in patients. These findings suggest that IC-driven pathways are both biologically significant and clinically relevant.
Understanding how kidney ICs actively regulate inflammation and repair marks a major shift in our perception of T1D-related kidney disease. Instead of suppressing the entire immune system, focusing on kidney-specific pathways could more effectively protect the kidneys while reducing side effects. Ultimately, this research may lead to new methods for maintaining kidney function in people with T1D and could also guide treatments for immune-related damage in other organs.
Description of Project
Nearly half of people with type 1 diabetes (T1D) develop kidney disease because the immune system that attacks insulin-producing cells can also mistakenly damage the kidneys, leading to ongoing renal inflammation. Damaged cells emit signals that attract and activate more immune cells, creating a harmful cycle that gradually worsens kidney function. Although most research has focused on immune damage to the kidney’s filtering units (glomeruli), much less is known about how other kidney cells affect inflammation, repair, and long-term disease. This knowledge gap limits the development of targeted treatments for T1D-related CKD.
The kidney contains specialized epithelial cells that support normal body function. Among them are intercalated cells (ICs), traditionally known for regulating acid–base balance. Recent evidence shows that ICs also act as “immune sentinels,” detecting tissue stress and communicating with immune cells. Understanding this role may explain why kidneys are damaged in T1D and could lead to new strategies to prevent injury.
One of the danger signals, UDP-glucose, in the kidney activates renal ICs through the P2Y14 receptor, leading to inflammation and the recruitment of immune cells. At the same time, ICs release IL-33 in response to kidney injury, a molecule that helps regulate immune responses by supporting regulatory T cells (Tregs), which typically act as “brakes” to prevent excessive or misguided immune attacks. In T1D, Tregs often do not function properly, allowing inflammation to persist. How ICs balance these harmful and protective signals—and how this balance breaks down—remains poorly understood.
The primary goal of this project is to understand how ICs regulate immune responses in T1D-associated autoimmune kidney disease through two main pathways: the inflammatory P2Y14 pathway and the immune-regulatory IL-33 pathway. We propose that ICs act as key coordinators, determining whether kidney injury leads to harmful inflammation or healing. When P2Y14 signaling dominates, inflammation increases, and kidney damage worsens. Conversely, when IL-33 signaling is properly activated, immune responses are controlled, repair processes begin, and kidney function is maintained. If this balance is disrupted, repair fails, resulting in persistent inflammation. Our previous research supports this hypothesis: blocking P2Y14 reduces kidney injury in a mouse model, suggesting this pathway could be targeted for therapy. Additionally, we found that urinary UDP-glucose levels can serve as a reliable marker of kidney injury in hospitalized patients with acute kidney injury, highlighting the clinical importance of this danger-sensing pathway.
In this project, using several mouse models, we will first analyze how ICs utilize P2Y14 to promote inflammation during T1D-associated autoimmune kidney injury. Next, we will examine how IL-33 derived from ICs supports Tregs, fostering immune tolerance and tissue repair. Together, these studies will uncover a previously unrecognized communication network between kidney epithelial cells and the immune system. We will translate our findings to patients with T1D by analyzing urine and blood samples from individuals at various stages of kidney disease. We will look for signals of epithelial cell stress (UDP-glucose and IL-33) that appear before kidney function declines and that predict disease progression. By detecting these early signals, our work aims to identify at-risk patients sooner and guide the development of new treatments that restore the balance between epithelial and immune cells before irreversible kidney damage occurs. Redefining T1D-associated kidney disease as an epithelial–immune disorder, this project opens new therapeutic pathways focused on restoring immune-epithelial balance. Identifying early epithelial-derived biomarkers will enable risk stratification, earlier intervention, and the selection of patients most likely to benefit from targeted therapies.
Anticipated Outcome
This research aims to deepen our understanding of how renal cells actively regulate immune responses during T1D-related autoimmune kidney diseases. By focusing on intercalated cells (ICs), a specialized type of kidney epithelial cell, this project shifts the current perspective of T1D autoimmune renal damage from one where immune cells alone cause harm to one where kidney epithelial cells also play a crucial regulatory role. The expected outcomes will provide new insights into why kidney inflammation becomes chronic in T1D and explore potential strategies to prevent or reverse it.
A key expected outcome is to identify the specific signaling pathways through which ICs promote harmful inflammation or protective immune regulation. By clarifying how the P2Y14 pathway in ICs triggers inflammatory responses and how IC-mediated IL-33 signaling supports immune tolerance and tissue repair, this research will explain how these processes are balanced in healthy kidneys and how that balance is disrupted in T1D. This knowledge will help clarify why kidney damage often persists even when blood glucose levels are controlled and systemic immune activity is suppressed.
Another expected outcome is to clarify how ICs communicate with various immune cell populations, including regulatory T cells (Tregs), which suppress inflammation. Understanding these communication pathways will reveal how immune cells are recruited, activated, or restrained within the kidney. Because Tregs are essential for controlling autoimmune damage in T1D, insights into how ICs support or fail to support Treg function may lead to new strategies for repairing kidney damage.
This project also aims to identify new opportunities for targeted therapy. Demonstrating that specific epithelial signaling pathways contribute to kidney inflammation may help develop kidney-specific treatments that block harmful signals, such as P2Y14 activation, while preserving or enhancing protective pathways like IL-33–mediated repair. Such strategies could reduce kidney injury without the broad side effects associated with systemic immunosuppression.
Furthermore, this research will improve tools for disease monitoring and classification. Since evidence indicates that urinary UDP-glucose levels reflect kidney injury, the project may support using epithelial-derived danger signals, UDP-glucose and IL-33, as noninvasive biomarkers for early detection of kidney inflammation or for tracking immune responses in T1D patients. We will observe stage-dependent increases in serum and urine levels of UDP-glucose and IL-33 as kidney injury progresses, indicating immune activation and epithelial responses. Linking these biomarkers with clinical measures of kidney function will help classify patients by disease stage and inflammatory activity. Earlier detection and more accurate monitoring could enable clinicians to intervene before permanent kidney damage occurs.
Finally, the expected outcomes extend beyond kidney disease. The mechanisms identified in this study may also be relevant to other organs affected by T1D. By demonstrating that tissue-specific epithelial cells actively influence immune responses, this research could transform how autoimmune diseases are studied and treated.
Overall, the anticipated outcomes of this work are to provide a clearer, more detailed understanding of T1D-associated autoimmune kidney disease, identify new therapeutic targets, and establish a foundation for more precise and effective treatments that preserve kidney function and improve long-term patient outcomes.
Relevance to T1D
Despite progress in glycemic management, chronic kidney disease (CKD) in type 1 diabetes (T1D) remains a significant challenge, highlighting an unmet clinical need. In T1D, kidney damage results not only from hyperglycemia but also from immune-driven inflammation. Understanding how kidney cells and the immune system communicate during early damage will help us uncover what drives the disease.
Our research aims to develop treatments specific to each stage of the disease, helping prevent its progression and improve patients’ long-term health and quality of life. We focus on how kidney cells and the immune system interact through key signals such as IL-33 and UDP-glucose. Understanding these early signals could help detect kidney issues sooner, better predict who is at risk, and guide the creation of new therapies to slow or stop kidney disease in people with type 1 diabetes.
We are exploring a new way to understand kidney disease in T1D. In T1D, the body’s immune system attacks itself, and certain kidney cells, called epithelial cells, play a key role in determining whether early damage heals or progresses to long-term kidney problems. Currently, we can only detect kidney issues after significant damage has already happened, and there are few treatments that prevent the disease from worsening. We still don’t know how kidney cells respond to signals and stress in T1D—whether they calm inflammation or worsen it—which makes early diagnosis and the development of precise treatments difficult.
This project highlights a previously overlooked contributor to kidney inflammation: renal epithelial intercalated cells (ICs). Although ICs mainly maintain acid–base balance, new evidence shows they also serve as immune sentinels. When organs are injured, damaged cells release danger signals, one of which is UDP-glucose. ICs detect UDP-glucose through the P2Y14 receptor, triggering inflammatory responses that recruit immune cells to the kidney. Prolonged or excessive P2Y14 activation in ICs can intensify inflammation and lead to tissue damage.
During injury, ICs also release IL-33, a signaling molecule that helps regulate immune responses and supports tissue repair. IL-33 influences various immune cell types, including regulatory T cells (Tregs), which normally suppress excessive immune activation. Treg dysfunction is a hallmark of T1D and contributes to ongoing inflammation and autoimmunity. The balance between inflammatory P2Y14 signaling and protective IL-33–mediated immune regulation may therefore determine whether kidney injury heals or leads to chronic disease.
This research’s significance for T1D lies in its focus on tissue-specific epithelia-immune communication mechanisms. By explaining how ICs recognize danger signals and coordinate immune responses in the kidney, this work addresses a key question: why pancreatic immune dysfunction leads to progressive kidney damage. Importantly, this epithelial-driven process likely occurs before immune cell activation, making it a target that can be engaged without broadly suppressing the immune system.
This project also has significant therapeutic implications. Current treatments for autoimmune kidney disease mainly rely on systemic immunosuppression or B-cell–targeted therapies, which can increase infection risks and cause side effects. Focusing on IC-specific pathways, such as P2Y14 and IL-33, could facilitate kidney-specific treatments that reduce inflammation while preserving normal immune function. Additionally, measuring urinary or blood levels of UDP-glucose and IL-33 as biomarkers of kidney injury may allow for earlier detection and improved monitoring of kidney involvement in T1D.
Overall, this research could transform our understanding of kidney disease in T1D by uncovering a common epithelial–immune pathway that drives inflammation and healing. By focusing on tissue-specific immune regulation, these findings might lead to more precise, safer, and more effective ways to preserve kidney function across various autoimmune diseases.