Anna Ollerstam

The hypothesis that adenosine acting on adenosine A1 receptors (A1R) regulates several renal functions and mediates tubuloglomerular feedback (TGF) was examined using A1R knockout mice. We anesthetized knockout, wild-type, and heterozygous mice and measured glomerular filtration rate, TGF response using the stop-flow pressure (P(sf)) technique, and plasma renin concentration. The A1R knockout mice had an increased blood pressure compared with wild-type and heterozygote mice. Glomerular filtration rate was similar in all genotypes. Proximal tubular P(sf) was decreased from 36.7 +/- 1.2 to 25.3 +/- 1.6 mmHg in the A1R+/+ mice and from 38.1 +/- 1.0 to 27.4 +/- 1.1 mmHg in A1R+/- mice in response to an increase in tubular flow rate from 0 to 35 nl/min. This response was abolished in the homozygous A1R-/- mice (from 39.1 +/- 4.1 to 39.2 +/- 4.5 mmHg). Plasma renin activity was significantly greater in the A1R knockout mice [74.2 +/- 14.3 milli-Goldblatt units (mGU)/ml] mice compared with the wild-type and A1R+/- mice (36.3 +/- 8.5 and 34.1 +/- 9.6 mGU/ml), respectively. The results demonstrate that adenosine acting on A1R is required for TGF and modulates renin release.

While macro- and microscopic kidney development appear to proceed normally in mice that lack Foxi1, electron microscopy reveals an altered ultrastructure of cells lining the distal nephron. Northern blot analyses, cRNA in situ hybridizations, and immunohistochemistry demonstrate a complete loss of expression of several anion transporters, proton pumps, and anion exchange proteins expressed by intercalated cells of the collecting ducts, many of which have been implicated in hereditary forms of distal renal tubular acidosis (dRTA). In Foxi1-null mutants the normal epithelium with its two major cell types - principal and intercalated cells - has been replaced by a single cell type positive for both principal and intercalated cell markers. To test the functional consequences of these alterations, Foxi1(-/-) mice were compared with WT littermates in their response to an acidic load. This revealed an inability to acidify the urine as well as a lowered systemic buffer capacity and overt acidosis in null mutants. Thus, Foxi1(-/-) mice seem to develop dRTA due to altered cellular composition of the distal nephron epithelium, thereby denying this epithelium the proper gene expression pattern needed for maintaining adequate acid-base homeostasis.

In the kidney, nitric oxide synthase (NOS) of the neuronal isoform (nNOS) is predominantly located in the macula densa cells. Unspecific chronic NOS inhibition in rats leads to elevated blood pressure (P(A)), associated with increased renal vascular resistance. This study was designed to examine the effect of chronic selective inhibition of nNOS with 7-nitro indazole (7-NI) on P(A), GFR, and the tubuloglomerular feedback (TGF) system. P(A) was repeatedly measured by a noninvasive tail-cuff technique for 4 wk in rats treated orally with 7-NI, and in control rats. After treatment, the animals were anesthetized and renal excretion rates, GFR, and TGF activity were determined. After 1 wk of 7-NI treatment P(A) was increased from 129+/-4 to 143 2 mmHg. GFR (1.85+/-0.1 vs. 1.97+/-0.2 ml/min in controls) was unchanged, but micropuncture studies revealed a more sensitive TGF than in controls. After 4 wk of 7-NI treatment P(A) was 152+/-4 mmHg, but no change in GFR (1.90+/-0.5 ml/min) or TGF sensitivity was detected. Acute administration of 7-NI to nontreated rats did not affect P(A), but decreased GFR (1.49+/-0.1 ml/min) and increased TGF sensitivity. In conclusion, chronic nNOS inhibition leads to increased P(A). Our results suggest that the elevated P(A) could be caused by an initially increased TGF sensitivity, leading to decreased GFR and an increased body fluid volume.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and poor translatability of available preclinical models. Here we generated spatially resolved transcriptome maps of human IPF (n = 4) and bleomycin-induced mouse pulmonary fibrosis (n = 6) to address these limitations. We uncovered distinct fibrotic niches in the IPF lung, characterized by aberrant alveolar epithelial cells in a microenvironment dominated by transforming growth factor beta signaling alongside predicted regulators, such as TP53 and APOE. We also identified a clear divergence between the arrested alveolar regeneration in the IPF fibrotic niches and the active tissue repair in the acutely fibrotic mouse lung. Our study offers in-depth insights into the IPF transcriptional landscape and proposes alveolar regeneration as a promising therapeutic strategy for IPF.