Password Reset
Forgot your password? Enter the email address you used to create your account to initiate a password reset.
Forgot your password? Enter the email address you used to create your account to initiate a password reset.
Takuto Chiba, PhD, Research Assistant Professor in the Division of Pediatric Nephrology at UPMC Children’s Hospital of Pittsburgh, was awarded a George M. O’Brien Kidney Resource Alliance Opportunity Pool Program (OKRA OPP) pilot grant to pursue a new line of investigation aimed at understanding how acute kidney injury (AKI) progresses to chronic kidney disease (CKD). The project is focused on understanding the cellular and molecular mechanisms that drive fibrosis in the kidney following injury, with the ultimate goal of identifying therapeutic targets that could mitigate long-term damage.
Exploring the Role of Pericytes in AKI-Related Fibrosis
At the core of Dr. Chiba’s research project are pericytes. Pericytes are specialized mesenchymal cells that attach to the endothelial layer of the microvasculature and play fundamental roles in the functionality of small blood vessels.
“Pericytes surround endothelial cells and help regulate blood flow and maintain proper function under normal physiological conditions,” says Dr. Chiba. “But following an acute kidney injury, they often become maladaptive.”
In response to injury, pericytes may detach from their usual location around capillaries and undergo a transformation into myofibroblasts — cells known to produce excess extracellular matrix and contribute to the formation of fibrotic lesions. This fibrotic remodeling of the vasculature in the kidney is what leads to chronic kidney disease.
“My main interest is in understanding how and why these maladaptive transformations occur,” says Dr. Chiba. “If we can define the signaling events that drive this process, we may be able to intervene before irreversible damage sets in.”
Investigating VEGF-R2 Signaling in Pericytes
Dr. Chiba’s OKRA-funded research project is investigating how the vascular endothelial growth factor receptor 2 (VEGF-R2), a signaling protein traditionally associated with endothelial cell proliferation and vascular development, may influence what happens to pericytes after an AKI occurs. Dr. Chiba’s work challenges this conventional understanding by focusing on VEGF-R2 signaling specifically within pericytes.
“VEGF-R2 and its functionality is very well known in the context of endothelial cells,” says Dr. Chiba. “But what we found in our prior work, unexpectedly, is that deleting this receptor specifically in pericytes actually protects against CKD in our small animal models. That result was the opposite of what we initially hypothesized, and it occurred in models of ischemia/reperfusion injury, obstructions, and in nephrotoxic-induced AKI.”
Dr. Chiba’s project has two specific aims. The first is to investigate how pericyte-specific VEGF-R2 signaling affects vascular integrity and inflammation during the AKI-to-CKD transition. The second aim is to examine whether disruptions in fatty acid metabolism — specifically the oxidation of short-chain fatty acids in pericytes — contribute to inflammation and subsequent fibrotic remodeling of the vasculature.
Therapeutic Implications and Long-Term Goals of the Research
While VEGF-R2 inhibitors already exist and are used as cancer therapeutics to block angiogenesis in tumor cells, the existing agents are not cell-type specific and would not be suitable for targeting pericytes alone – and specifically pericytes only in the vasculature of the kidneys.
“Because VEGF-R2 is so important for endothelial cell function systemically in the human body, global inhibition could produce serious off-target or side effects,” says Dr. Chiba. “That is why I am interested in developing strategies that target VEGF-R2 only in pericytes, and if possible, only in the kidney."
Although the development of a potential therapeutic component lies beyond the immediate scope of this one-year pilot grant, the findings from Dr. Chiba’s work could lead to future translational efforts. In the near term, Dr. Chiba hopes to generate high-quality preliminary data to support an R01 application.
A Basic Science Approach to a Pediatric Problem
Dr. Chiba, a developmental biologist by training, was drawn to the field of kidney regeneration after becoming interested in how damaged tissues try to repair themselves because regeneration often recapitulates developmental machinery. In some organs, like the liver, regeneration is quite robust. But for the kidney and other organs like the heart or pancreas the capacity for cellular regeneration after an injury or illness is limited.
“For the kidney, part of the challenge lies in the complexity of the nephron and its structural specialization. When that cellular architecture is disrupted, as happens in AKI, it is very difficult for the kidney to reorganize itself,” says Dr. Chiba.
Dr. Chiba’s research is of particular importance when it comes to kidney injury in premature newborns or very young children.
“Neonates specifically, but also very young children have immature kidney function and are especially vulnerable to AKI and subsequent progression to CKD should they sustain an AKI,” says Dr. Chiba. “We need to better understand the mechanisms that drive long-term complications so we can develop more effective preventive strategies.”
A Platform for Future Investigation
The OKRA pilot grant mechanism is designed to support early-career investigators. It provides both funding and recognition to pursue high-risk, high-reward questions that can generate the foundational data necessary for larger NIH funding.
“In our field, there are no therapies available to stop or reverse the progression from AKI to CKD – in children and adults, alike, and it’s not for a lack of research effort to date. It’s just a very complex process,” says Dr. Chiba. “Clinically, we rely on supportive care and hope the damage does not progress. That clearly is not enough.”
With this project, Dr. Chiba hopes to identify specific molecular events in pericytes that can be modulated to prevent fibrosis after AKI and preserve long-term kidney function.
“My work in this area is still early-stage,” says Dr. Chiba. “But if we can isolate the signaling pathways and metabolic triggers that turn pericytes into drivers of fibrosis, it could eventually lead to more targeted approaches that change how we manage AKI and its downstream effects — especially in children.”
Selection of Prior Published Research from Dr. Chiba
Dr. Chiba’s postdoctoral training in the laboratory of Sunder Sims-Lucas, PhD, at UPMC Children’s focuses on lipid metabolism and AKI. For further reading, the studies linked below are relevant to his current independent project on how dysregulated metabolism in renal pericytes contributes to CKD.
1. Chiba et al., J Am Soc Nephrol. 2019. Sirtuin 5 Regulates Proximal Tubule Fatty Acid Oxidation to Protect against AKI. (PMID: 31575700)
2. Chiba et al., JCI Insight. 2025. Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury. (PMID: 39932791)