27 research outputs found
Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies
Diabetic kidney disease (DKD) occurs in âŒ40% of patients with diabetes and causes kidney failure, cardiovascular disease, and premature death. We analyzed the response of a murine DKD model to five treatment regimens using single-cell RNA sequencing (scRNA-seq). Our atlas of âŒ1 million cells revealed a heterogeneous response of all kidney cell types both to DKD and its treatment. Both monotherapy and combination therapies targeted differing cell types and induced distinct and non-overlapping transcriptional changes. The early effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the S1 segment of the proximal tubule suggest that this drug class induces fasting mimicry and hypoxia responses. Diabetes downregulated the spliceosome regulator serine/arginine-rich splicing factor 7 (Srsf7) in proximal tubule that was specifically rescued by SGLT2i. In vitro proximal tubule knockdown of Srsf7 induced a pro-inflammatory phenotype, implicating alternative splicing as a driver of DKD and suggesting SGLT2i regulation of proximal tubule alternative splicing as a potential mechanism of action for this drug class
Overexpression of angiotensin-converting enzyme in myelomonocytic cells enhances the immune response [version 1; referees: 3 approved]
Angiotensin-converting enzyme (ACE) converts angiotensin I to the vasoconstrictor angiotensin II and thereby plays an important role in blood pressure control. However, ACE is relatively non-specific in its substrate specificity and cleaves many other peptides. Recent analysis of mice overexpressing ACE in monocytes, macrophages, and other myelomonocytic cells shows that these animals have a marked increase in resistance to experimental melanoma and to infection by Listeria monocytogenes or methicillin-resistant Staphylococcus aureus (MRSA). Several other measures of immune responsiveness, including antibody production, are enhanced in these animals. These studies complement a variety of studies indicating an important role of ACE in the immune response
Salt sensitivity in response to renal injury requires renal angiotensin-converting enzyme
Recent evidence indicates that salt-sensitive hypertension can result from a subclinical injury that impairs the kidneysÂŽ capacity to properly respond to a high-salt diet. However, how this occurs is not well understood. Here, we showed that although previously salt-resistant wild-type mice became salt sensitive after the induction of renal injury with the nitric oxide synthase inhibitor NÏ-nitro-l-arginine methyl ester hydrochloride; mice lacking renal angiotensin-converting enzyme, exposed to the same insult, did not become hypertensive when faced with a sodium load. This is because the activity of renal angiotensin-converting enzyme plays a critical role in (1) augmenting the local pool of angiotensin II and (2) the establishment of the antinatriuretic state via modulation of glomerular filtration rate and sodium tubular transport. Thus, this study demonstrates that the presence of renal angiotensin-converting enzyme plays a pivotal role in the development of salt sensitivity in response to renal injury.Fil: Giani, Jorge Fernando. Cedars Sinai Medical Center; Estados Unidos. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Bernstein, Kenneth E.. Cedars Sinai Medical Center; Estados UnidosFil: Janjulia, Tea. Cedars Sinai Medical Center; Estados UnidosFil: Han, Jiyang. Keck School Of Medicine Of Usc; . University of Southern California; Estados UnidosFil: Toblli, Jorge Eduardo. Universidad de Buenos Aires; Argentina. Hospital AlemĂĄn. Laboratorio de Medicina Experimental; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Shen, Xiao Z.. Cedars Sinai Medical Center; Estados UnidosFil: Rodriguez Iturbe, Bernardo. Cedars Sinai Medical Center; Estados Unidos. Hospital Universitario de Maracaibo; VenezuelaFil: McDonough, Alicia A.. University of Southern California; Estados UnidosFil: Gonzalez Villalobos, Romer A.. Cedars Sinai Medical Center; Estados Unido