Beneficial effect on podocyte number in experimental diabetic nephropathy resulting from combined atrasentan and RAAS inhibition therapy

Abstract

Podocyte loss and proteinuria are both key features of human diabetic nephropathy (DN). The leptin-deficient BTBR mouse strain with the ob/ob mutation develops progressive weight gain, type 2 diabetes, and diabetic nephropathy that has many features of advanced human DN, including increased mesangial matrix, mesangiolysis, podocyte loss, and proteinuria. Selective antagonism of the endothelin-1 type A receptor (ETAR) by atrasentan treatment in combination with renin-angiotensin-aldosterone system inhibition with losartan has been shown to have the therapeutic benefit of lowering proteinuria in patients with DN, but the underlying mechanism for this benefit is not well understood. Using a similar therapeutic approach in diabetic BTBR ob/ob mice, this treatment regimen significantly increased glomerular podocyte number compared with diabetic BTBR ob/ob controls and suggested that parietal epithelial cells were a source for podocyte restoration. Atrasentan treatment alone also increased podocyte number but to a lesser degree. Mice treated with atrasentan demonstrated a reduction in proteinuria, matching the functional improvement reported in humans. This is a first demonstration that treatment with the highly selective ETAR antagonist atrasentan can lead to restoration of the diminished podocyte number characteristic of DN in humans and thereby underlies the reduction in proteinuria in patients with diabetes undergoing similar treatment. The benefit of ETAR antagonism in DN extended to a decrease in mesangial matrix as measured by a reduction in accumulations of collagen type IV in both the atrasentan and atrasentan + losartan-treated groups compared with untreated controls.

The Pathology Lesion Patterns of Podocytopathies: How and why?

“…Several studies suggested that the presence of PECs on the glomerular tuft represents an attempt to replenish the podocyte pool (Romoli et al, 2018;Lasagni et al, 2015;Peired et al, 2013;Kaverina et al, 2019;Eng et al, 2015;Zhang et al, 2013;Kaverina et al, 2020). The capacity of a PEC subset to differentiate into podocytes and restore the podocyte number is the likely explanation for the clinical observations of remission and regression of functional parameters of chronic kidney disease in patients with diabetic and nondiabetic nephropathies (Cortinovis et al, 2016;Fioretto et al, 1998;Remuzzi et al, 2006;Takahashi et al, 2007), as well as for podocyte number restoration observed in response to pharmacological treatment in experimental models of diabetic and non-diabetic kidney disease (Zhang et al, 2012;Hudkins et al, 2020;Zhang et al, 2015). Recent results elucidated the podocyte-progenitor cross-talk revealing mediators of progenitor quiescence during homeostasis and mechanisms by which podocyte loss triggers the activation of the progenitor population in the setting of podocyte injury (Peired et al, 2021).…”

Imaging the Kidney with an Unconventional Scanning Electron Microscopy Technique: Analysis of the Subpodocyte Space in Diabetic Mice

“…Since it is known that the enlargement of SPS increases the mechanical forces exerted on podocytes by water filtration and induces podocyte detachment from the glomerular basement membrane [14] and that BTBR ob/ob mice were characterised by a significant loss of podocytes [19,20,24,25], we then identified and analysed the ultrastructure In diabetic mice, the mean SPS area per podocyte was significantly higher than in BTBR WT mice (Figure 6H) and was almost seven times higher than in the control WT group.…”

“…Since it is known that the enlargement of SPS increases the mechanical forces exerted on podocytes by water filtration and induces podocyte detachment from the glomerular basement membrane [14] and that BTBR ob/ob mice were characterised by a significant loss of podocytes [19,20,24,25], we then identified and analysed the ultrastructure of these cells in BTBR ob/ob mice. Consistent with previous data [26], diabetic BTBR ob/ob mice were characterised by hypertrophic changes in podocytes.…”

Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle?

“…Injuries to podocytes are considered an important contributor to diabetic kidney disease progression toward end-stage kidney disease [39][40][41]. Suganami et al reported the prevention and reversal of renal injury by leptin administration in animal models of diabetic nephropathy [39].…”

“…In particular, the leptin treatment, but not RAAS-I, resulted in a significant increase in podocyte density and number and in an increase of WT1-positive proliferating PEC. The mechanisms underlying this process was further delineated in a follow-up paper, where they showed that a dual treatment of leptin-deficient ob/ob mice with a selective antagonist of the endothelin-1 type A receptor (ETAR) in combination with RAAS inhibition led to an improved phenotype [40], characterized by the activation of PECs and increased number of podocytes. These results provide indirect evidence that PECs may be a potential reservoir to restore lost podocytes and that the differentiative capacity of PECs may be a key element for the regression of diabetic nephropathy that might be pharmacologically modulated.…”