Project title
腎臟血管周邊細胞在急性腎損傷—慢性腎病連續症的命運與角色 (III)
Internal ID
NHRI-EX113-11139SI
Principal Investigator
Start Date
January 1, 2024
End Date
December 31, 2024
Organizations
Partner Organizations
National Health Research Institutes
The fate and role of kidney pericytes during acute kidney injury–chronic kidney disease continuum (III) = 腎臟血管周邊細胞在急性腎損傷—慢性腎病連續症的命運與角色 (III)
Keywords
acute kidney injury
chronic kidney disease
kidney pericyte
Description
Acute kidney injury (AKI) is an important disease or complication with high mortality. The most effective intervention is to prevent AKI so that the AKI-associated mortality can be avoided. Acute dialysis therapy can support AKI patients with uremia, but how to reduce AKI-associated mortality and complications is still an unmet clinical need. Moreover, the conventional wisdom that patients will lead a life without significant kidney disease if they recover from AKI after a prompt treatment may not be right because more and more studies found that high proportion of AKI patients develop chronic kidney disease (CKD) and progress to end-stage renal disease (ESRD) during follow-up in outpatient clinics even though they survive to be discharged from hospital without significant impairment of kidney function. Therefore, subclinical AKI might be a critical piece of the CKD unknown etiology puzzle. Epidemiological studies have demonstrated the impact of AKI severity, pre-existing CKD, and the other chronic disease such as diabetes mellitus and hypertension on withdrawal of acute dialysis therapy, and incident CKD, progression to ESRD after renal recovery from AKI episode. The development of CKD after AKI impacts on not only individual health, increase of mortality due to cardiovascular disease and infection, but also on family, society, and economy. In patients with glomerulonephritis with AKI, immunosuppressive therapy may be effective to improve kidney function. But in patients with AKI due to the other etiologies, most of the clinically available treatments, including acute dialysis, are supportive to wait for the spontaneous repair and regeneration of kidneys after injury. No treatment of proven efficacy can be used clinically to promote the repair and regeneration. By analyzing our National Taiwan University Hospital Acute Renal Failure Study Cohort (NSARF), we have demonstrated the association of treatment with renin-angiotensin system (RAS) inhibitor in patients after total renal recovery from cardiac surgery-associated AKI with lower possibility of CKD development during follow-up. To prove the efficacy of RAS inhibitor in the prevention of CKD after AKI, we generated a murine model of AKI-CKD continuum and demonstrated that starting losartan, an antagonist for angiotensin II receptor 1a, after renal recovery from AKI can prevent CKD and prolong survival. Our previous studies have proven the role of pericytes in renal fibrosis, scaring, and atrophy of mice with progressive kidney disease. Pericytes are one of cell types expressing angiotensin II receptor 1a. We recently proved that pericytes are activated and proliferate in the kidneys of mice after AKI. In the kidneys with functional recovery, ~20% of the pericytes remain and retain the higher potential for cell proliferation and scar formation, lose the function for microvascular stabilization, and promote CKD progression thereafter. Mechanistically, transforming growth factor-1 decreases the binding of YBX2 to the promoter of Acta2 and induces Ybx2 hypermethylation, thereby increasing -smooth muscle actin expression in pericytes. Demethylation by 5-azacytidine recovers the microvascular stabilizing function of activated pericytes, reverses the profibrotic property of inactivated pericytes, prevents AKI-CKD transition, and attenuates fibrogenesis. Because the activated pericytes increase in cell numbers and enclose the injured renal tubules in the acute phase with 7 days after AKI, and undergo apoptosis during renal recovery, we hypothesize that activated pericytes might promote renal recovery through stabilizing the structure and promoting the repair/regeneration of the injured tubular epithelial cells. Our pilot experiments showed that renal recovery is hindered by anti-PDGFR antibody-mediated pericyte inhibition, activated pericytes highly express Cxcl12 and Col1a1 genes. Because the expression of C-X-C motif chemokine receptor 4 (CXCR4) and discoidin domain receptor 1 (DDR1), receptors for CXCL12 and type I collagen respectively, increases in the injured tubular epithelial cells, we are intrigued by the function and role of activated pericytes in the recovery of AKI. In this 3-year grant proposal, we would like to use the murine model of AKI to study: (a) the role of kidney pericytes in the repair and regeneration of injured tubular epithelial cells after AKI by specific pericyte ablation; (b) the role of pericyte-derived growth factor CXCL12 in the repair and regeneration of injured tubular epithelial cells after AKI by pericyte-specific CXCL12 knockout or exogenous CXCL12 administration; (c) the role of pericyte-derived type I collagen/tubular epithelial DDR1 signaling in the repair and regeneration of injured tubular epithelial cells after AKI by pericyte-specific Col1a1 knockout or administration of DDR1 inhibitor. Clarifying the roles of pericytes and applying the beneficial therapies in specific time points of AKI-CKD will be the first step for precision medicine to promote AKI recovery and stop CKD progression.