The prorenin receptor (PRR) is highly expressed in podocytes, but its role in the maintenance of podocyte function is unknown. Here we generated podocyte-specific PRR-knockout mice and found that these animals died between 2 to 3 wk after birth. Within 14 d, PRR-knockout mice developed nephrotic syndrome, albuminuria with podocyte foot-process fusion, and cytoskeletal changes. Podocyte-specific PRR deletion also led to disturbed processing of multivesicular bodies and enrichment of autophagosomal (LC3) and lysosomal (LAMP2) markers, indicating a functional block in autophagosome-lysosome fusion and an overload of the proteasomal protein-degradation machinery. In vitro, PRR knockdown and pharmacologic blockade of vacuolar H ϩ -ATPases, which associate with the PRR, increased vesicular pH, led to accumulation of LC3-positive and LAMP2-positive vesicles and altered the cytoskeleton. Taken together, these results suggest that the PRR is essential for podocyte function and survival by maintaining autophagy and protein-turnover machinery. Furthermore, PRR contributes to the control of lysosomal pH, which is important for podocyte survival and cytoskeletal integrity.

No abstract

Peroxisome proliferator-activated receptor-␥ (PPAR-␥) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against nondiabetic chronic kidney disease in experimental models. Here, we found that the PPAR-␥ agonist pioglitazone protected against renal injury in aging; it reduced proteinuria, improved GFR, decreased sclerosis, and alleviated cell senescence. Increased local expression of PPAR-␥ paralleled these changes. Underlying mechanisms included increased expression of klotho, decreased systemic and renal oxidative stress, and decreased mitochondrial injury. Pioglitazone also regulated p66Shc phosphorylation, which integrates many signaling pathways that affect mitochondrial function and longevity, by reducing protein kinase C-␤. These results suggest that PPAR-␥ agonists may benefit aging-related renal injury by improving mitochondrial function.

Abstract Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients.

Previously we found thymosin β4 (Tβ4) is up-regulated in glomerulosclerosis and required for angiotensin II-induced expression of plasminogen activator inhibitor-1 (PAI-1) in glomerular endothelial cells. Tβ4 has beneficial effects in dermal and corneal wound healing and heart disease yet its effects in kidney disease are unknown. Here we studied renal fibrosis in wild type and PAI-1 knockout mice following unilateral ureteral obstruction to explore the impact of Tβ4 and its prolyl oligopeptidase tetrapeptide degradation product, Ac-SDKP, in renal fibrosis. Additionally, we explored interactions of Tβ4 with PAI-1. Treatment with Ac-SDKP significantly decreased fibrosis in both wild type and PAI-1 knockout mice, as observed by decreased collagen and fibronectin deposition, fewer myofibroblasts and macrophages, and suppressed pro-fibrotic factors. In contrast, Tβ4 plus a prolyl oligopeptidase inhibitor significantly increased fibrosis in wild type mice. Tβ4 alone also promoted repair and reduced late fibrosis in wild type mice. Importantly, both pro-fibrotic effects of Tβ4 plus the prolyl oligopeptidase inhibitor, and late reparative effects of Tβ4 alone, were absent in PAI-1 knockout mice. Thus, Tβ4 combined with prolyl oligopeptidase inhibition, is consistently pro-fibrotic, but by itself, has anti-fibrotic effects in late stage fibrosis, while Ac-SDKP has consistent anti-fibrotic effects in both early and late stages of kidney injury. These effects of Tβ4 are dependent on PAI-1.