Four-and-a-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is a microvascular complication that leads to kidney dysfunction and ESRD, but the underlying mechanisms remain unclear. Podocyte Wnt-pathway activation has been demonstrated to be a trigger mechanism for various proteinuric diseases. Notably, four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in urogenital systems and has been implicated in Wnt/b-catenin signaling. Here, we used in vitro podocyte culture experiments and a streptozotocin-induced DKD model in FHL2 gene-knockout mice to determine the possible role of FHL2 in DKD and to clarify its association with the Wnt pathway. In human and mouse kidney tissues, FHL2 protein was abundantly expressed in podocytes but not in renal tubular cells. Treatment with high glucose or diabetes-related cytokines, including angiotensin II and TGF-b1, activated FHL2 protein and Wnt/b-catenin signaling in cultured podocytes. This activation also upregulated FHL2 expression and promoted FHL2 translocation from cytosol to nucleus. Genetic deletion of the FHL2 gene mitigated the podocyte dedifferentiation caused by activated Wnt/b-catenin signaling under Wnt-On, but not under Wnt-Off, conditions. Diabetic FHL2 +/+ mice developed markedly increased albuminuria and thickening of the glomerular basement membrane compared with nondiabetic FHL2 +/+ mice. However, FHL2 knockout significantly attenuated these DKD-induced changes. Furthermore, kidney samples from patients with diabetes had a higher degree of FHL2 podocyte nuclear translocation, which was positively associated with albuminuria and progressive renal function deterioration. Therefore, we conclude that FHL2 has both structural and functional protein-protein interactions with b-catenin in the podocyte nucleus and that FHL2 protein inhibition can mitigate Wnt/b-catenin-induced podocytopathy. 26: 3072-3084, 201526: 3072-3084, . doi: 10.1681 Diabetic kidney disease (DKD) is the leading cause of ESRD, affecting 10%-40% of diabetic patients, and the cost of RRT remains a large economic burden for the health care system. Proteinuria is a major and primary clinical aspect of DKD and causes tubulointerstitial lesions that lead to renal dysfunction. 1 Reducing proteinuria may therefore be a principal therapeutic target to improve renal outcome in patients with DKD. However, the pathophysiologic mechanism of DKD is multifactorial, and some patients develop treatment-resistant proteinuria that results in ESRD despite intensive BP and glycemia control. Thus, identification of major DKD mechanisms and development of new therapeutic options are needed. Glomerular epithelial cells, also called podocytes, are predominantly responsible for maintaining the glomerular filtration barrier. Podocytes are highly specialized, terminally differentiated cells that cannot proliferate. 2 Recently, hyperactive podocyte J Am Soc Nephrol

FHL2 promotes tubular epithelial‐to‐mesenchymal transition through modulating β‐catenin signalling

“…It should be pointed out that FHL2 could be a coactivator or corepressor of β‐catenin depending on cell types . In one recent study, FHL2 presents as a coactivator of Wnt/β‐catenin signalling in podocytes in DKD . Consistently, our data suggest that FHL2 has both physical and functional interactions with β‐catenin in the tubular epithelial cells undergoing EMT.…”

“…It should be pointed out that FHL2 could be a coactivator or corepressor of b-catenin depending on cell types [19]. In one recent study, FHL2 presents as a coactivator of Wnt/b-catenin signalling in podocytes in DKD [23]. Consistently, our data suggest that FHL2 has both FHL2 is predominantly expressed in muscle and cardiovascular systems, and it can also be found in tissues of different origin [20].…”

“…FHL2 is predominantly expressed in muscle and cardiovascular systems, and it can also be found in tissues of different origin . Recent study shows that FHL2 expression is abundant in podocytes in adult kidney tissue, and its expression is up‐regulated by high glucose and cytokines associated with DKD, such as angiotensin II and TGF‐β1 . However, it is barely reported regarding its expression and function in tubular epithelial cells, especially in certain pathologic states, for example tubular EMT.…”

Kidney Response to Heart Failure: Proteomic Analysis of Cardiorenal Syndrome

“…RAGE is a multiligand receptor from immunoglobulin family that binds amyloids, S100 proteins and advanced glycation end-products (AGEs) that accumulate in tissues with aging, diabetes or renal insufficiency [21,32]. In kidneys, RAGE is expressed in podocytes, endothelial and mesangial cells and RAGE activation triggers proinflammatory response and promotes nephropathy [33].…”

Increasing the level of peroxisome proliferator-activated receptor γ coactivator-1α in podocytes results in collapsing glomerulopathy

“…Mice were placed on doxycycline-containing chow (Bio Serv S3888) starting at 4 weeks of age. Type 1 diabetes was induced by daily intraperitoneal injections of streptozotocin (Sigma-Aldrich), 50 mg/kg for 5 days, in 6-week-old male mice (56). Only male mice were used in the study.…”