Wu, Ellen-1, Macklin, Sarah, Zhang, Yanling, Thai, Kerri, Nghiem, Linda, Di Ciano‐Oliveira, Caterina, Coelho, Nuno, Wang, Hai, Advani, Suzanne L., Desjardins, Jean‐François, Yuen, Darren A, Misra, Paraish, Connelly, Kim A., Nyengaard, Jens R. and Gilbert, Richard E. (2025) Induction of proximal tubular proliferation and lengthening in response to sodium glucose linked cotransporter‐2 inhibition in experimental rats. Journal of Diabetes Investigation. ISSN 2040-1116

Abstract

Aims/Introduction
While SGLT2 accounts for >90% of kidney glucose reabsorption, its pharmacological inhibition or genetic knockdown reduces glucose reabsorption by only 50%.

Materials and Methods
We postulated that the less than expected glucosuric response to SGLT2 inhibition might result from a compensatory increase in the length of the proximal tubule as seen in experimental diabetes where early tubular proliferation is followed by tubular lengthening. Taking advantage of their differing anatomical locations, stereological techniques were used to differentiate the SGLT1 expressing straight proximal tubule that lies within the outer stripe of the outer medulla (S3 segment) and that of the predominantly SGLT2 expressing early proximal convoluted tubule located within the kidney cortex (S1, S2 segments).

Results
The SGLT2 inhibitor, dapagliflozin, induced an early, transient hyperplastic response (3-fold increase of Ki67 labelling, P < 0.0001) in S3 proximal tubular cells followed by a 32% increase in its length (P < 0.0001). In contrast, the length of the SGLT2 expressing S1, S2 segments of the proximal tubule was unaffected.

Conclusions
The finding that SGLT2 inhibition leads to expansion of the S3 segment of the proximal tubule, the site of SGLT1, is suggestive of a physiological response to diminish urinary glucose loss akin to that occurring in experimental diabetes. These findings provide a cogent explanation for the less-thanthan-expected effect of this drug class on glucose reabsorption.

Item Type:	Article
Date Deposited:	08 May 2025 00:45
Last Modified:	08 May 2025 00:45
URI:	https://oak.novartis.com/id/eprint/57305