Shroom3, a Gene Associated with CKD, Modulates Epithelial Recovery after AKI

Abstract

Background: Ischemia induced acute kidney injury (AKI) resulting in tubular damage can often progress to chronic kidney disease (CKD) and is a common cause of nephrology consultation. Following renal tubular epithelial damage, molecular and cellular mechanisms are activated to repair and regenerate the damaged epithelium. If these mechanisms are impaired, AKI can progress to CKD. Even in patients whose kidney function returns to normal baseline are more likely to develop CKD. Genome-wide association studies have provided robust evidence that genetic variants in SHROOM3, which encodes an actin-associated protein, are associated with CKD and poor outcomes in transplanted kidneys. Here, we sought to further understand the associations of Shroom3 in CKD. Methods: Kidney ischemia was induced in wild-type and Shroom3 heterozygous null mice (Shroom3Gt/+) and the mechanisms of cellular recovery and repair were examined. Results: A 28-minute bilateral ischemia in Shroom3Gt/+ mice resulted in 100% mortality within 24 hours. After 22-minute ischemic injury, Shroom3Gt/+ mice had a 16% increased mortality, worsened kidney function, and significantly worse histopathology, apoptosis, proliferation, inflammation, and fibrosis after injury. The cortical tubular damage in Shroom3Gt/+ was associated with disrupted epithelial redifferentiation, disrupted Rho-kinase/myosin signaling, and disorganized apical F-actin. Analysis of Madin Darby Canine Kidney Cells showed the levels of Shroom3 are directly correlated to apical organization of actin and actomyosin regulators. Conclusion: These findings establish that Shroom3 is required for epithelial repair and redifferentiation through the organization of actomyosin regulators and could explain why genetic variants in Shroom3 are associated with CKD and allograft rejection.

Global analysis of cell behavior and protein dynamics reveals region-specific roles for Shroom3 and N-cadherin during neural tube closure

“…Interestingly, our analysis suggests that anterior shroom3 crispant cells fail to constrict less from a lack of actomyosin accumulation and more from an inability to accumulate N-cadherin at the medial surface of cells. This is consistent with a previously reported genetic interaction between shroom3 and N-cadherin ( Lang et al, 2014 ; Li et al, 2021 ; Plageman et al, 2011b ), and suggests that a Shroom3-N-cadherin pathway may drive anterior apical constriction during neural tube closure. The function of this N-cadherin remains to be determined, but two possibilities are suggested by prior studies.…”

Spatial Multi-Omics Connect SHROOM3 and COL18A1 in Chronic Kidney Disease

“…9 Following acute kidney injury, Shroom3 heterozygous knockout mice displayed increased mortality, worsened kidney function, and heightened fibrosis. 10 Studies in different animal models show similar results: post-natal Shroom3 knockdown induces albuminuria in mice, reintroducing the normal Shroom3 gene into hypertensive rats alleviates albuminuria and glomerulosclerosis, and introducing wild-type Shroom3 into Shroom3 -deficient zebrafish remedies glomerular abnormalities. 11,12 Despite these insights, the comprehensive impact of the SHROOM3 gene on kidney disease, relevant biomarkers, and underlying mechanism remains incompletely understood.…”

The Good and the Bad of SHROOM3 in Kidney Development and Disease: A Narrative Review

“…35,55 Additional studies confirm consistency in protein expression in some, but not all, epithelial cells in the apical regions of the initial S1 segment of the proximal tubule, distal convoluted tubule, and medullary collecting ducts. 56,57 Studies have also demonstrated Shroom3 mRNA expression in the pronephric tubules in zebrafish, the pronephric duct in Xenopus , and in the glomeruli of both. 5,58 RNA-sequencing in human adult tissue showed spatial expression of SHROOM3 transcripts in kidney glomeruli and tubules.…”

“…This altered recovery was due to disrupted Rho-kinase signaling and actin disorganization that resulted in disrupted epithelial differentiation of the tubular epithelium. 57 The changes in Shroom3 expression in heterozygous null mice could also have effects with age. The analysis of 1-year-old Shroom3 heterozygous null mice exhibit glomerulosclerosis and smaller podocytes with foot process flattening and effacement.…”