Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice

Abstract

Nephropathy develops in many but not all patients with longstanding type 1 diabetes. Substantial efforts to identify genotypic differences explaining this differential susceptibility have been made, with limited success. Here, we show that the expression of the transforming growth factor β1 gene (Tgfb1) affects the development of diabetic nephropathy in mice. To do this we genetically varied Tgfb1 expression in five steps, 10%, 60%, 100%, 150%, and 300% of normal, in mice with type 1 diabetes caused by the Akita mutation in the insulin gene (Ins2 Akita ). Although plasma glucose levels were not affected by Tgfb1 genotype, many features of diabetic nephropathy (mesangial expansion, elevated plasma creatinine and urea, decreased creatinine clearance and albuminuria) were progressively ameliorated as Tgfb1 expression decreased and were progressively exacerbated when expression was increased. The diabetic 10% hypomorphs had comparable creatinine clearance and albumin excretion to wild-type mice and no harmful changes in renal morphology. The diabetic 300% hypermorphs had ∼1/3 the creatinine clearance of wild-type mice, >20× their albumin excretion, ∼3× thicker glomerular basement membranes and severe podocyte effacement, matching human diabetic nephropathy. Switching Tgfb1 expression from low to high in the tubules of the hypomorphs increased their albumin excretion more than 10-fold but creatinine clearance remained high. Switching Tgfb1 expression from low to high in the podocytes markedly decreased creatinine clearance, but minimally increased albumin excretion. Decreasing expression of Tgfb1 could be a promising option for preventing loss of renal function in diabetes.aldosterone | glomerular filtration rate | glomerulosclerosis | megalin | nephrin D iabetes is the number one cause of end-stage renal disease in the United States and many other developed countries. However, despite having similar levels of blood glucose only 20-40% of all diabetic patients develop diabetic nephropathy. In diabetic nephropathy, increased expression of transforming growth factor β1 (TGFβ1) has been demonstrated to promote accumulation of extracellular matrix components (1), apoptosis (2), dedifferentiation of podocytes (3), and epithelial-mesenchymal transition of proximal tubules (4), all of which are thought to facilitate a decline in nephron number and renal function.Tgfb1-null mice on a mixed genetic background show severe multiorgan inflammation with massive infiltration of lymphocytes and macrophages that culminates in death by 3-4 wk of age (5, 6). Their death effectively prevents determining whether absence of TGFβ1 influences the development of nephropathy. To overcome this problem and also to allow the study of the effects of above-normal TGFβ1, we have generated mice with five genetically graded levels of TGFβ1, and have made them diabetic with the Ins2 Akita mutation, which causes pancreatic beta-cell dysfunction and type 1 diabetes.Here we show that the features characteristic of diabetic nephropathy are progressively ...

Transforming Growth Factor-Beta1 in Diabetic Kidney Disease

“…Moreover, RamachandraRao et al (2009) found that pirfenidone decreased TGF-β promoter activity, blocked TGF-β1 production, and was effective in reducing mesangial matrix expansion and fibrosis in DKD. Switching TGF-β1 expression from low to high by genetic manipulation exacerbated renal injury in Akita mice, a result that further supported the idea that blockade of TGF-β1 was renoprotective for DKD (Hathaway et al, 2015). The success of TGF-β1 signaling inhibition in animal studies has promoted the strategy in clinical investigations with DKD (Sharma et al, 2011;Voelker et al, 2017).…”

“…TGF-β1 also suppresses reabsorption of glucose by proximal epithelial cells. A dose-dependent increase in TGF-β1 expression by genetic manipulation increased urinary output of glucose in Akita mice, whereas genetic insufficiency of TGF-β1 decreased glucose output (Hathaway et al, 2015). Moreover, SGLT2 was directly regulated by TGF-β1 via Smad3 (Panchapakesan et al, 2013) and TGF-β1 showed decreased expression of SGLT1 and SGLT2 (Lee and Han, 2010).…”

Transforming growth factor β1 antagonizes the transcription, expression and vascular signaling of guanylyl cyclase/natriuretic peptide receptor A – role of δEF1

“…Studies using targeted disruption of the Npr1 gene in mice have shown enhanced activation of pro‐inflammatory cytokines, including TGF‐β1, in the heart and kidneys . In contrast, activated TGF‐β1 has been shown to participate in the pathogenesis of cardiac hypertrophy, renal fibrosis and vascular remodeling via its downstream signaling pathway . The findings of the present study demonstrate that TGF‐β1 induces the expression of δEF1 and its binding to the Npr1 promoter, thus repressing Npr1 gene transcription, expression and function in the physiological context.…”

“…Transforming growth factor β1 (TGF‐β1) belongs to the TGF‐β family of peptides, which regulate various cellular processes such as proliferation, differentiation, apoptosis, and specification of cell type during embryonic development . Hypertension, nephropathy and cardiac hypertrophy are associated with significantly elevated levels of TGF‐β1 and collagen in Npr1 gene knockout mice . Previous findings indicated that TGF‐β1 decreased Npr1 mRNA levels in cultured aortic smooth muscle cells; however, the underlying molecular mechanisms were not determined .…”

Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

“…Both mRNA and protein levels of TGF-β1 are significantly elevated in DN patients [14,15]. Studies from experimental diabetic animals further substantiated the role of TGF-β1 in the pathogenesis of DN [16]. Neutralizing antibodies against TGF-β1 reversed the type II diabetic renal injury [17].…”